Substituted phenyl compounds, and pharmaceutical composition and use thereof

Abstract

The present application relates to substituted phenyl compounds, a pharmaceutical composition thereof and the use thereof. Specifically, provided are substituted phenyl compounds represented by formula (I), which can be used for preparing drugs, especially drugs used for preventing and / or treating Kv1.3 channel-mediated diseases or disorders, each group in formula (I) being as defined in the description.

Description

Substituted phenyl compounds, pharmaceutical compositions and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024110836155, filed on August 8, 2024, Chinese Patent Application No. 2024115751577, filed on November 6, 2024, Chinese Patent Application No. 2024116809912, filed on November 22, 2024, Chinese Patent Application No. 202510042388X, filed on January 10, 2025, Chinese Patent Application No. 2025103170816, filed on March 18, 2025, Chinese Patent Application No. 2025108003576, filed on June 16, 2025, and Chinese Patent Application No. 2025110819864, filed on August 1, 2025. This application incorporates the entirety of the above-mentioned Chinese Patent Applications. TECHNICAL FIELD

[0002] The present application belongs to the field of medicine, and specifically relates to a substituted phenyl compound, a pharmaceutical composition and uses thereof, which can be used as a Kv1.3 channel inhibitor. BACKGROUND

[0003] Kv1.3 channel is one of the members of Kv family, which was first discovered in human T lymphocytes, and is expressed in the immune system, nervous system and vascular smooth muscle cells. Kv1.3 is one of the main potassium ion channels found in T cells, and its main function is to regulate the membrane potential. In the process of antigen presentation, Kv1.3 channels gather on the synapses of immune cells and promote Ca 2+ signaling.

[0004] Studies have shown that Kv1.3 is mainly involved in the activation process of effector T cells, so different subtypes of T cells have different sensitivities to Kv1.3 inhibitors. Selective inhibition of Kv1.3 channels can selectively inhibit the activation process of effector T cells, which provides a new idea for the treatment of autoimmune diseases related to effector T cells. Kv1.3 has thus become a new target protein for the treatment of autoimmune diseases such as multiple sclerosis, type I diabetes, psoriasis, contact dermatitis, rheumatoid arthritis and myasthenia gravis.

[0005] Kv1.3 channels also play a role in gastroenterological disorders, including inflammatory bowel diseases ("IBD") such as ulcerative colitis ("UC") and Crohn's disease. UC is a chronic IBD characterized by excessive T cell infiltration and cytokine production. UC can impair quality of life and can lead to life-threatening complications. High Kv1.3 channel levels in CD4 and CD8 positive T cells in inflamed mucosa of UC patients have been associated with the production of pro-inflammatory compounds in active UC. Kv1.3 channels are considered a marker of disease activity and pharmacological blockade can constitute a new immunosuppressive strategy for UC.

[0006] Peptide toxins with Kv1.3 inhibitory effect have been isolated from scorpions, sea anemones, and Dalazatide (ShK-186) derived from non-natural amino acids has shown certain therapeutic effect in the treatment of psoriasis in phase Ib clinical trials, but the poor subtype selectivity and the problem of oral administration of peptide molecules limit the application of this type of molecules. Therefore, it is of great value to develop highly selective, orally available small molecule Kv1.3 inhibitors.

[0007] Currently published patents related to Kv1.3 channel inhibitors (blockers) include WO2022076285A1, WO2022251561A2, WO2021071821A1 and WO2021071812A1, etc. SUMMARY

[0008] The present application provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] T is C 3-10 cycloalkyl, C 3-10 cycloalkenyl or 3-10 membered heterocyclyl, said C 3-10 cycloalkyl, C 3-10 cycloalkenyl or 3-10 membered heterocyclyl is optionally substituted with one or more R 7 substituents;

[0011] Ring A is 5-10 membered heteroaryl;

[0012] Z is OH;

[0013] R 1 , R 2 , R 3 and R 4 are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano and amino;

[0014] R 5 is selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 3-12 cycloalkyloxy, C 3- 12 cycloalkylthio, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, -S(O)2R e , -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthio, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy and 3-12 membered heterocyclylthio are optionally substituted with one or more R g ;

[0015] R j and R k are the same or different and each is independently selected from the group consisting of H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0016] or, R j and Rk with the atom to which it is attached, form a 3-6 membered carbocyclic or 3-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo;

[0017] R g are the same or different and each is independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , NR b R c , -S(O)2R e , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy, which C 1-6 alkyl, C 3-6 cycloalkyl, C 3- 6cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy are optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 alkoxy, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0018] R 6 are the same or different and each is independently selected from H, deuterium, halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-8 membered heteroaryl;

[0019] or, R 5 and one of R6 , or two R 6 and the atom to which they are attached form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C(O)R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0020] R 7 are the same or different and each is independently selected from H, deuterium, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0021] or, two R 7 and the atom to which they are attached form a 3-6 membered carbocyclic or 3-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo;

[0022] or, one R 7 and R 5 , or one R 7 and one R 6 any of which groups, together with the atom to which they are attached, form a 3-12 membered carbocyclic or 3-12 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0023] R a and R d are the same or different and each is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, OH, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0024] R b and R c are the same or different and each is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0025] or R b and R c together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo;

[0026] R e is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0027] n is 0, 1, or 2;

[0028] r is 0, 1, 2, 3, 4, 5, and 6.

[0029] In some embodiments, the heteroatoms in the heteroaryl, heterocyclyl, heterocyclic ring, heterocyclyloxy, and heterocyclylmercapto groups are independently selected from O, N, and S, in a number of 1, 2, 3, 4, or 5.

[0030] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein,

[0031] T is C 3-10 cycloalkyl, or 3-10 membered heterocyclyl, which C 3-10Cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more R 7 substituents;

[0032] Ring A is 5-10 membered heteroaryl;

[0033] Z is OH;

[0034] R 1 , R 2 , R 3 , and R 4 are the same or different and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano, and C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano, and amino;

[0035] R 5 is selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, -S(O)2R e , -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d , and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, and 3-12 membered heterocyclylmercapto is optionally substituted with one or more R g substituents;

[0036] R jand R k are the same or different and each is independently selected from the group consisting of H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0037] or, R j and R k together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo;

[0038] R g are the same or different and each is independently selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , -S(O)2R e , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- alkoxy, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0039] R 6the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0040] or, two R 5 and one R 6 , two R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1- cyanoalkyl, cyano, amino, oxo, C(O)R a , C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0041] R 7 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0042] or, two R 7 form, together with the atom to which they are attached, a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl being optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino and oxo;

[0043] or, one R 7 and R 5 , or one R 7 and one R6 any one of the groups together with the atoms to which it is attached form C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0044] R a and R d are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, OH, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0045] R b and R c are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0046] or R b and R c together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclyl, said 4-8 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino and oxo;

[0047] R e is selected from C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0048] n is 0, 1, or 2;

[0049] r is 0, 1, 2, 3, 4, 5, and 6.

[0050] In some embodiments, compounds are represented by formula (I), or pharmaceutically acceptable salts thereof, wherein R 7 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0051] or, two R 7 and the atoms to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo;

[0052] or, one R 7 and R 5 , or one R 7 and one R 6 any group form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0053] In some embodiments, compounds are represented by formula (I), or pharmaceutically acceptable salts thereof, wherein R 5 is selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy group, 3-12 membered heterocyclic mercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkyloxy, C 3-12 Cycloalkyl mercapto, 3-12-membered heterocyclic group, 3-12-membered heterocyclic oxygen group and 3-12-membered heterocyclic mercapto group are optionally surrounded by one or more R g replace;

[0054] R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -S(O)2R e C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0055] Or, R 5 And one of the R 6 Two Rs 6 The atoms bonded to it form C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3- 12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C(O)R a C 3-6 The cycloalkyl group and one or more substituents of the 3-6 membered heterocyclic group are substituted;

[0056] R a R b R c Rd R e R j R k And r are as defined above.

[0057] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, C 3-6 cycloalkyl and C 3-6 Halogenated cycloalkyl groups.

[0058] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 Replace, R 7 As defined above.

[0059] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 7 replace;

[0060] R 7 They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0061] Or, one of the R 7 and R 5 , or one of the R 7 And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl.

[0062] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is 5-membered heteroaryl.

[0063] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, deuterium, halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and 3-12 membered heterocyclylmercapto are optionally substituted with one or more R g ;

[0064] R g are the same or different and each is independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , C 3-6 cycloalkyl, C 3-6cycloalkyl, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy.

[0065] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0066] or, R 5 and one of R 6 and the atom to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0067] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R 7 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, and amino;

[0068] or, R 7 and R 5 , or R 7 and R 6 any of which groups, together with the atom to which they are attached, form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1- hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0069] In some embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof, wherein,

[0070] T is C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more R 7 substituents;

[0071] Ring A is 5-membered heteroaryl;

[0072] R 5 is selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthiol, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthiol, -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthiol, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and 3-12 membered heterocyclylthiol is optionally substituted with one or more R g substituents;

[0073] R g are the same or different and each is independently selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;

[0074] R 6 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0075] or, R 5 and one of R 6 and the atom to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0076] R 7 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano and amino;

[0077] or, one of R 7 and R 5 , or one of R 7 and one of R 6 any of the groups forms a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0078] R a , R b , R c and R d are as defined above.

[0079] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, satisfies one or more of the following conditions:

[0080] (1) each of said "C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 aminoalkyl, and C 1-6 cyanoalkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl, preferably methyl, ethyl, i-propyl, or s-butyl, for example methyl;

[0081] (2) each of said "C 1-6 alkyl, and C 1-6 haloalkyl" is independently fluorine, chlorine, bromine, or iodine, preferably fluorine, chlorine, or bromine, for example fluorine;

[0082] (3) each of said "C 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 cycloalkyloxy, and C 3-12 cycloalkylmercapto" is independently C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl, or cyclopentyl, for example cyclopentyl or cyclopropyl;

[0083] each of said "C 3-6 cycloalkyl, and C 3-6 cycloalkyloxy" is independently cyclopentyl or cyclopropyl;

[0084] (4) each of said 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl, 4-8 membered heterocyclyl, 3-10 membered heterocyclyl, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy is independently N, O, or S, for example N or O; the number of said heteroatoms independently can be 1 or 2;

[0085] said "3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl, and 3-10 membered heterocyclyl" is independently preferably 3-8 membered heterocyclyl, more preferably 4-8 membered heterocyclyl;

[0086] The heterocyclic groups in the "3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group, and 3-6-membered heterocyclic oxy group" can independently be saturated or partially unsaturated monocyclic, bridged, fused, or spirocyclic, such as aza-heterobutyl, oxo-heterobutyl, tetrahydrofuranyl, tetrahydropyrroleyl, tetrahydrothiaranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, etc.

[0087] (5) The 5-10-membered heteroaryl, 5-8-membered heteroaryl and 5-membered heteroaryl are preferably 5-membered heteroaryl, wherein the heteroatom is N, O or S, preferably N and O, for example N; the number of heteroatoms can be 1, 2, 3 or 4, for example 2 or 3, for example triazolyl, tetrazolyl, thiazolyl, pyrazolyl, imidazole and oxazolyl;

[0088] (6) Each of the C's descriptions 3-10 The cycloalkenyl group is independently C 5-6 Cycloalkenyl;

[0089] (7) Each of the C's descriptions 2-6 The alkenyl group is independently C 2-4 Alkenyl groups, such as vinyl groups; and

[0090] (8) Each of the C's descriptions 2-6 The alkynyl group is independently C 2-4 Alkyne group, such as ethynyl group.

[0091] In some embodiments, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein T is selected from... The a-terminus is attached to a phenyl group; m is 0, 1, 2, 3, 4, 5, and 6; h is 0, 1, 2, 3, and 4; j is 0, 1, 2, 3, and 4; R 8 Selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, and oxo; R 7 As defined by compound (I);

[0092] Preferably, j is 0, h is 0, m is 0, 1, or 2, and R 7 For deuterium, halogens, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, -C 1-6alkylene-3-6 membered heterocyclyl or 3-6 membered heterocyclyl.

[0093] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, T is selected from m is 0, 1, 2, 3, and 4; a is attached to the phenyl; R 7 as defined for a compound of Formula (I).

[0094] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, T is selected from m is 0, 1, 2, 3, and 4; a is attached to the phenyl; R 7 as defined for a compound of Formula (I).

[0095] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, T is

[0096] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, T is m is 0, 1, 2, 3, and 4; R 7 as defined above.

[0097] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof, T is preferably is

[0098] In some embodiments, the compound of Formula (I) is a compound of Formula (IIG):

[0099] wherein,

[0100] G is selected from the group consisting of absent, CR 7b R 7c , NR 7e , O, and S;

[0101] u is 1 and 2;

[0102] v is 0, 1, and 2;

[0103] R 7a , R 7b , R 7c , and R 7d are the same or different and each is independently selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0104] R 7e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, -C 1-6 alkylene-3-6-membered heterocyclic group, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups;

[0105] Or, R 7b and R 7c The atoms bonded to it form C 3-6 cycloalkyl or 3-6 membered heterocyclic groups, wherein the C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo;

[0106] Or, R 7a and R 5 、or R 7a And one of the R 6 Any group of atoms bonded to it forms C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups, wherein the C 3-12 Cycloalkyl or 3-12 membered heterocyclic groups are optionally selected from halogens, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 Cyanoalkyl, cyano, amino, oxo, C 3-6 The cyclic alkyl group is replaced by one or more substituents in the 3-6 membered heterocyclic group;

[0107] R 1 R 2 R 3 R 4 R 5 R 6 R 7, ring A, m and n are as defined for a compound of Formula (I).

[0108] In some embodiments, a compound of Formula (IIG) or a pharmaceutically acceptable salt thereof, wherein G is CR 7b R 7c , R 7b and R 7c are H.

[0109] In some embodiments, a compound of Formula (IIG) or a pharmaceutically acceptable salt thereof, wherein v and m are independently 0, 1 or 2.

[0110] In some embodiments, a compound of Formula (IIG) is a compound of Formula (II),

[0111] wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7a , R 7b , R 7c , R 7d , ring A and n are as defined for a compound of Formula (IIG).

[0112] In some embodiments, a compound of Formula (I) is a compound of Formula (II), wherein, R 7a , R 7b , R 7c and R 7d are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0113] or either R 7a and R 5 , or R 7a and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0114] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring A and n are as defined for compounds of Formula (I).

[0115] In some embodiments, a compound of Formula (I), Formula (IIG), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazolyl (e.g. ), imidazolyl (e.g. ), pyrazolyl (e.g. ), oxazolyl, thiazolyl, isoxazolyl (e.g. ), tetrazolyl (e.g. ), pyridinyl (e.g. ,

[0116] In some embodiments, a compound of Formula (I), Formula (IIG), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazolyl, imidazolyl, pyrazolyl, oxazolyl, and thiazolyl.

[0117] In some embodiments, a compound of Formula (I), Formula (IIG), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein ring A is selected from triazolyl, imidazolyl, pyrazolyl, isoxazolyl, tetrazolyl, and pyridinyl, preferably from triazolyl (e.g. ) and imidazolyl (e.g. ).

[0118] In some embodiments, a compound of Formula (I), Formula (IIG), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein is selected from R 5 and R 6 are as defined for compounds of Formula (I).

[0119] In some embodiments, a compound of Formula (I), Formula (IIG), or Formula (II), or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, C1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, -S(O)2R e , -C(O)R a , -CH2-N(R b )C(O)R d and -CH2-C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy and 3-8 membered heterocyclylmercapto are optionally substituted with one or more R g ;

[0120] R 6 are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl and 3-6 membered heterocyclyl;

[0121] Alternatively, R 5 and one of R 6 , two R 6 with the atoms to which they are attached form a 4-12 membered heterocyclyl, said 4-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C(O)R a , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R g , R a , R b , R c , R d , R e , R j , R kand R g are as defined above.

[0122] In some embodiments, the compound of Formula (I) is a compound of Formula (II-1),

[0123] wherein R 7a , R 7b , R 7c and R 7d are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; preferably, R 7a , R 7b , R 7c and R 7d are the same or different and each is independently selected from H, F, CH3, CH2NH2, CH2CN, azetidinyl, piperidinyl, and

[0124] R 5 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, -S(O)2R e , C(O)R a , -CH2-N(R b )C(O)R d , and -CH2-C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylmercapto are optionally substituted with one or more R g ;

[0125] R 6the same or different, and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-8 membered heteroaryl;

[0126] or R 7a and R 5 form a 4-12 membered heterocyclyl with the atom to which they are attached, which is optionally substituted with one or more substituents selected from halogen, OH, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0127] R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R e , R j , R k and R g are as defined for the compound of Formula (I).

[0128] In some embodiments, a compound is represented by Formula (II), or a pharmaceutically acceptable salt thereof, wherein is selected from R 5 , R 6 , R 7 , R 7b , R 7c , R 7d and m are as defined above.

[0129] In some embodiments, a compound is represented by Formula (II-1), or a pharmaceutically acceptable salt thereof, wherein is selected from R 5 , R 6 , R 7b , R 7c and R 7d are as defined above.

[0130] In some embodiments, the compound of Formula (I) is a compound of Formula (II-2),

[0131] R 7a , R 7b , R 7c , and R 7d are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; preferably, R 7a , R 7b , R 7c , and R 7d are the same or different and each is independently selected from H, F, CH3, CH2OH, CH2CN, azetidinyl, piperidinyl, and

[0132] R 5 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, C(O)R a , -CH2-N(R b )C(O)R d , and -CH2-C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylmercapto is optionally substituted with one or more R g ;

[0133] R 6 are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6cycloalkyl, 3-6 membered heterocyclyl, and 5-8 membered heteroaryl;

[0134] or, R 7a and R 5 , or R 5 and its adjacent R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 4-12 membered heterocyclyl, said C 3-12 cycloalkyl or 4-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0135] R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d and R g are as defined for the compound of Formula (I).

[0136] In some embodiments, the compound of Formula (II-2) or a pharmaceutically acceptable salt thereof, is represented by Formula (II-2a): 5 and its adjacent R 6 form, together with the atom to which they are attached, a 5-10 membered heterocyclyl, said 5-10 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0137] In some embodiments, the compound of Formula (I), Formula (II), and Formula (II-2) or a pharmaceutically acceptable salt thereof, is represented by Formula (II-2a): is selected from

[0138] In some embodiments, the compound of Formula (I) is represented by Formula (II-3):

[0139] R 7a , R7b R 7c and R 7d are the same or different and each is independently selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; preferably, R 7a , R 7b , R 7c and R 7d are the same or different and each is independently selected from the group consisting of H, F, CH3, CH2OH, CH2CN, azetidinyl, piperidinyl, and

[0140] R 5 is selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, C(O)R a , -CH2-N(R b )C(O)R d , and -CH2-C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylmercapto being optionally substituted with one or more R g ;

[0141] R 6 are the same or different and each is independently selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-8 membered heteroaryl;

[0142] or, R 7a and R 6 , or R 5 and R6 any one of R and R forms, together with the atoms to which they are attached, a 4-12 membered heterocyclyl group optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;

[0143] R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d and R g are as defined for the compound of Formula (I).

[0144] In some embodiments, the compound of Formula (II-3) or a pharmaceutically acceptable salt thereof, wherein R 7a and R 6 , or R 5 and R 6 form, together with the atoms to which they are attached, a 5-10 membered heterocyclyl group optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1- 6haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0145] In some embodiments, the compound of Formula (II-3) or a pharmaceutically acceptable salt thereof, wherein is selected from R v are the same or different, each independently selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; p is 0, 1, 2, 3, and 4.

[0146] In some embodiments, the compounds represented by formulas (II), (II-1), (II-2), and (II-3), or pharmaceutically acceptable salts thereof, wherein R 7a R 7b R 7c and R 7d They may be the same or different, and each is independently selected from H, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Cyanoalkyl, C 1-6 aminoalkyl, C 1-6 Hydroxyl, OH, cyano, and amino.

[0147] In some implementation schemes, where Selected from R u Selected from H, C 1-6 Alkyl and C(O)R a ;R 6 and R a As defined above.

[0148] In some embodiments, the compound represented by formula (I) is the same as the compound represented by formula (III).

[0149] R 1 R 2 R 3 R 4 R 5 R 6 And T is as defined above.

[0150] In some embodiments, the compounds represented by formula (I), formula (IIG), formula (II-1), formula (II-2), formula (II-3), and formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-12 cycloalkyl, C 3-12 Cycloalkenyl, C 3-12 Cycloalkyloxy, 3-12-membered heterocyclic, 5-8-membered heteroaryl, 3-12-membered heterocyclic oxy, 3-12-membered heterocyclic mercapto, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c The C mentioned1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkenyl, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy and 3-12 membered heterocyclyl are optionally substituted with one or more R g substituents;

[0151] R j and R k together with the atom to which they are attached form a 3-6 membered heterocyclic ring;

[0152] R g are the same or different and each is independently selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, amino, oxo, =NH, C(O)R a , NR b R c , 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy, said C 1-6 alkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen and C 1-6 alkoxy;

[0153] R a and R d are the same or different and each is independently selected from the group consisting of C 1-6 alkyl and 3-6 membered heterocyclyl;

[0154] R b and R c are selected from the group consisting of H and C 1-6 alkyl, or R b and R c together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring; said 4-8 membered heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of OH and C 1-6 alkyl;

[0155] r is 0 or 1.

[0156] In some embodiments, the compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from the group consisting of H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C3-12 Cycloalkenyl and 3-12 membered heterocyclyl are optionally substituted with one or more R g substituents;

[0157] R g are the same or different, and each is independently selected from -NH2, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, and oxo.

[0158] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 is selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, C(O)R a , -CH2-N(R b )C(O)R d , and -CH2-C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylmercapto are optionally substituted with one or more R g substituents; R a , R b , R c , R d , and R g are as defined above; and / or, R 6 are the same or different, and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl.

[0159] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 6 are the same or different, and each is independently selected from deuterium, halogen, C1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, -S(O)2R e and C 3-6 cycloalkyl;

[0160] R e selected from C 1-6 alkyl;

[0161] n is 0 or 1.

[0162] In some embodiments, a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 6 are the same or different and each is independently selected from deuterium, halogen, and C 1-6 alkyl;

[0163] n is 0 or 1.

[0164] In some embodiments, a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from CH3, CN, (CH2)3OH, CHF2, CF3, Cl, S(O)2CH3, Br, D, F, or cyclopropyl;

[0165] n is 0 or 1. In some embodiments, a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-2), and Formula (II-3), or a pharmaceutically acceptable salt thereof, wherein R 5 and the R 6 adjacent thereto, or two adjacent R 6 , and the atoms to which they are attached form a 5-10 membered heterocycle, which is optionally substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 hydroxyalkyl, and -C(O)-C 1-6 alkyl.

[0166] In some embodiments, a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-2), and Formula (II-3), or a pharmaceutically acceptable salt thereof, wherein R 5 and the R 6 adjacent thereto, or two adjacent R 6 , and the atoms to which they are attached form a ( denotes a bond common to ring A.

[0167] In some embodiments, compounds of Formula (I) and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 7 are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, -C 1-6 alkylene-3-6 membered heterocyclyl, and 3-6 membered heterocyclyl; preferably H.

[0168] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein R 7 and R 5 , or R 7 and R 6 , and the atoms to which they are attached form a 5-10 membered heterocyclic ring.

[0169] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts thereof, wherein R 7 and R 5 , or R 7 and R 6 , and the atoms to which they are attached form denotes a site common to T, denotes a bond common to ring A.

[0170] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 5 is selected from H, (CH2) t NH2, O-(CH2) t NH2, (CH2) t OH, cyclopropyl, t is 1, 2, 3, 4, 5, and 6;

[0171] and / or, R 6 are the same or different and each is independently selected from H, deuterium, C 1-3 alkyl, cyano, and S(O)2CH3.

[0172] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R5 For

[0173] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , and R 4 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, cyano, and C 2-6 alkynyl.

[0174] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are CI, R 3 is H, and R 4 is selected from H, CN, and ethynyl.

[0175] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , and R 4 are the same or different and each is independently selected from H, halogen, and C 1-6 alkyl.

[0176] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , and R 4 are the same or different and each is independently selected from H, halogen, and cyano.

[0177] In some embodiments, compounds of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are each CI, R 3 and R 4 are H; or R 2 and R 3the same or different, and each independently Cl or methyl, R 1 and R 4 are each H.

[0178] In some embodiments, the compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), and Formula (III), or a pharmaceutically acceptable salt thereof, wherein

[0179] In some embodiments, the compound of Formula (I) and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 the same or different, and each independently selected from H, deuterium, F, CH3, CH2OH, CH2CN, azetidinyl, piperidinyl, and

[0180] In some embodiments, the compound of Formula (I) and Formula (III), or a pharmaceutically acceptable salt thereof, wherein R 7 the same or different, and each independently selected from H, F, CH3, CH2OH, and CH2CN.

[0181] In some embodiments, the compound of Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), and Formula (II-3), or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c and R 7d the same or different, and each independently selected from H, F, CH3, CH2OH, CH2CN, azetidinyl, piperidinyl, and

[0182] In some embodiments, the compound of Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), and Formula (II-3), or a pharmaceutically acceptable salt thereof, wherein R 7a , R 7b , R 7c and R 7d the same or different, and each independently selected from H, F, CH3, CH2OH, and CH2CN.

[0183] Exemplary specific compounds of the compounds of the present application include, but are not limited to, the structures in Table A below:

[0184] Table A ​

[0185] Exemplary specific compounds of the compounds shown in the present application include, but are not limited to, the structures in Table B below:

[0186] Table B

[0187] Another aspect of the present application provides a compound shown in formula (C) or a pharmaceutically acceptable salt thereof,

[0188] wherein R A is a hydroxyl protecting group, for example, methyl, -SEM ((trimethylsilyl)ethoxymethyl), -TBS (tert-butyldimethylsilyl), -MOM (methoxymethyl), -MEM (2-methoxyethoxymethyl), -THP (2-tetrahydropyran), and the like;

[0189] R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined for the compound of formula (I).

[0190] In some embodiments, the compound shown in formula (C) is selected from the following compounds:

[0191] Another aspect of the present application provides a method for preparing a compound of formula (IIIA), comprising subjecting a compound shown in formula (A) to a ring closure reaction with a compound shown in formula (B) to obtain a compound shown in formula (C1), followed by a deprotection reaction to obtain a compound shown in formula (IIIA), according to the following reaction scheme:

[0192] Among them, R A The hydroxyl protecting group is, for example, methyl, -SEM ((trimethylsilyl)ethoxymethyl), -TBS (tert-butyldimethylsilyl), -MOM (methoxymethyl), -MEM (2-methoxyethoxymethyl), -THP (2-tetrahydropyran), etc.

[0193] R 1 R 2 R 3 R 4 and R 5 As defined by compound (I).

[0194] In another aspect, this application provides isotope labels for compounds shown in Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), as well as those shown in Table A or Table B, wherein the isotope label is preferably deuterium (D or... 2 H) replaces hydrogen ( 1 H).

[0195] In another aspect, this application provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0196] In another aspect, this application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for inhibiting the Kv1.3 channel.

[0197] In another aspect, this application also provides the use of compounds of formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), shown in Table A or Table B, or pharmaceutically acceptable salts thereof, or isotopic labels thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for blocking Kv1.3 channels.

[0198] In another aspect, the present application provides the use of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and / or treatment of a Kv1.3 channel-mediated disease.

[0199] The present application also provides the use of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention and / or treatment of an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease, or a cancer, for example, in the manufacture of a medicament for the prevention and / or treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, nephritis, chronic kidney disease, kidney fibrosis, inflammatory neuropathy, and ischemic stroke.

[0200] The present application also provides a method of inhibiting a Kv1.3 channel, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form thereof, or a pharmaceutical composition comprising the same.

[0201] The present application also provides a method of blocking a Kv1.3 channel, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form thereof, or a pharmaceutical composition comprising the same.

[0202] The present application also provides a method of preventing and / or treating a Kv1.3 channel-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form thereof, or a pharmaceutical composition comprising the same.

[0203] The present application also provides a method for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease, or a cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the foregoing.

[0204] The present application also provides a method for preventing and / or treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn’s disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy, and ischemic stroke, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the foregoing.

[0205] The present application also provides a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the foregoing, for use as a medicament.

[0206] The present application also provides a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the foregoing, for use as a Kv1.3 channel inhibitor.

[0207] The present application also provides a compound of Formula (I), Formula (IIG), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), and Formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotopically-labeled form of the foregoing, or a pharmaceutical composition comprising the foregoing, for use as a Kv1.3 channel blocker.

[0208] The present application also provides a compound as shown in formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotope-labeled compound thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating a Kv1.3 channel-mediated disease or disorder.

[0209] The present application also provides a compound as shown in formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotope-labeled compound thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer.

[0210] The present application also provides a compound as shown in formula (I), formula (IIG), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III) and formula (IIIA), or a pharmaceutically acceptable salt thereof, or an isotope-labeled compound thereof, or a pharmaceutical composition comprising the same, for use as a medicament for preventing and / or treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy and ischemic stroke.

[0211] The Kv1.3 channel-mediated disease described in the present application is selected from an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a renal disease, a central nervous system disease or a cancer.

[0212] The Kv1.3 channel-mediated disease described in the present application is selected from rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, renal fibrosis, inflammatory neuropathy and ischemic stroke.

[0213] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0214] In some embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0215] In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound of Formula (I), Formula (II), Formula (II-1) and Formula (II-2), Formula (II-3), Formula (III), Formula (IIIA), Table A or Table B or a pharmaceutically acceptable salt thereof or an isotopically-labeled material thereof.

[0216] In some embodiments, the pharmaceutical composition contains 0.01%-99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of one or more pharmaceutically acceptable excipients.

[0217] As a pharmaceutical, the compounds of the present application can be administered in the form of pharmaceutical compositions. These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration can be topical (e.g., transdermal, transcutaneous, opthalmic and mucosal including intranasal, vaginal and rectal), pulmonary (e.g., through the use of an inhaler or insufflator; intratracheal, intranasal), oral or parenteral. Parenteral administration includes subcutaneous, intravenous, intraarterial, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. Parenteral administration can be by single doses, or by continuous infusion via, e.g., a minipump.

[0218] In making the compositions of the application, the active ingredient is typically mixed with an excipient, which can take a wide variety of forms depending on the form of composition desired for administration. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0219] The "excipient" as used herein refers to an ingredient other than the active ingredient, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, and lubricants.

[0220] In another aspect, pharmaceutically acceptable salts of the compounds described herein can be inorganic or organic salts, acid addition salts if the compounds have a basic center, base addition salts if the compounds have an acid center, and internal salts if the compounds contain both an acid center and a basic center (e.g., a carboxylate group and a tertiary nitrogen).

[0221] In another aspect, the compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such isomers, including cis and trans isomers, (-)- and (+)-enantiomeric forms, (R)- and (S)-enantiomeric forms, diastereomeric forms, (D)- isomer forms, (L)-isomer forms, racemic mixtures and other mixtures, and enantiomeric or diastereomeric enrichments thereof, all of which are intended to be within the scope of the present application. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers, as well as mixtures thereof, are included in the present application.

[0222] In the chemical structures of the compounds described herein, a bond indicates unspecified configuration, indicates absolute configuration, i.e., if chiral isomers are present in the chemical structure, a bond may be or both configurations, indicates the presence of an axial chirality.

[0223] a bond indicates unspecified configuration, including either the cis (E) or trans (Z) configuration.

[0224] In addition, the compounds and intermediates of the present application can exist in different tautomeric forms, and all such forms are embraced within the scope of the present application. "Tautomers" refer to different energy structures that can interconvert via a low energy barrier. For example, prototropic tautomers (also known as proton-shift tautomers) include interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactim isomerization. All tautomeric forms of all compounds of the present application are within the scope of the present application. The name of a compound named in a single form does not exclude any tautomers.

[0225] The present application also includes isotopically-labeled compounds of the present application which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H,​11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, and the like. All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0226] Unless otherwise indicated, when a position is designated specifically as deuterium (D), the position is understood to have deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 10% deuterium incorporation). Exemplary compounds having deuterium in an abundance of at least 1000 times greater than the natural abundance of deuterium can have deuterium in an abundance of at least 2000 times greater than the natural abundance of deuterium, at least 3000 times greater than the natural abundance of deuterium, at least 4000 times greater than the natural abundance of deuterium, at least 5000 times greater than the natural abundance of deuterium, at least 6000 times greater than the natural abundance of deuterium, or greater. Each available hydrogen atom attached to a carbon atom can be independently replaced with a deuterium atom. Those skilled in the art are capable of synthesizing compounds in deuterated form by reference to the literature. In preparing deuterated forms of compounds, the deuterated starting materials are either commercially available or they can be synthesized using conventional techniques employing deuterated reagents including, but not limited to, deuterated borane, trideuteroborane in tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide, and deuterated methyl iodide, and the like.

[0227] The "therapeutic effective amount" in this application refers to the amount of an active compound or drug that researchers, veterinarians, physicians, or other clinicians seek in tissues, systems, animals, individuals, or humans to elicit a biological or medical response. It includes one or more of the following: (1) prevention of disease: e.g., prevention of disease, disorder, or condition in individuals susceptible to disease, disorder, or symptom but not yet experiencing or exhibiting the pathology or symptoms of the disease; (2) inhibition of disease: e.g., inhibition of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., prevention of further development of the pathology and / or symptoms); (3) relief of disease: e.g., relief of disease, disorder, or symptom in individuals experiencing or exhibiting the pathology or symptoms of the disease, disorder, or symptom (i.e., reversal of the pathology and / or symptoms). For the purposes of this application, "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate effective amount in a particular case can be determined by a person skilled in the art based on routine testing.

[0228] "Pharmaceutical acceptable" in this application means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0229] In this application, "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, with human being being the most preferred. Beneficial effects

[0230] This application provides a small molecule compound that can be used as a Kv1.3 channel inhibitor (blocker), and such compounds or pharmaceutical compositions can be used to effectively treat or prevent Kv1.3 channel-mediated diseases.

[0231] Terminology Definitions and Explanations

[0232] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0233] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms (C 1-6alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, s-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and various branched isomers thereof, and the like. Alkyl groups can be substituted or unsubstituted.

[0234] The term "alkenyl" is to be understood as preferably denoting a straight-chained or branched hydrocarbon group which contains one or more double bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkenyl". "C 2-10 The term "alkenyl" is to be understood as preferably denoting a straight-chained or branched monovalent hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl". "C 2-3alkenyl). It is to be understood that in case the alkenyl group comprises more than one double bond, the double bonds can be separated from each other or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl. The alkenyl group can be substituted or unsubstituted.

[0235] The term "alkynyl" is to be understood as meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2 to 20 carbon atoms, preferably "C 2-10 alkynyl". The term "C 2-10 alkynyl" is to be understood as preferably meaning a straight-chain or branched one- valent hydrocarbon group which comprises one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, for example, 2, 3, 4, 5 or 6 carbon atoms (i.e. "C 2- 6alkynyl"), 2 or 3 carbon atoms ("C 2-3The term "alkynyl" refers to a straight or branched hydrocarbon chain that contains one or more triple bonds. The alkynyl group preferably contains from 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms (e.g., 2, 3, 4, 5, 6, 7, and 8 carbon atoms), and even more preferably 2 to 6 carbon atoms. The alkynyl group can be substituted or unsubstituted. Examples of alkynyl groups include ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl group is ethynyl, prop-1-ynyl, or prop-2-ynyl. The alkynyl group can be substituted or unsubstituted.

[0236] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, and butyloxy. The alkoxy group can be substituted or unsubstituted. 1-12 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, and butyloxy. The alkoxy group can be substituted or unsubstituted. 1- The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined herein. Preferred are alkoxyl groups containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms. More preferred are alkoxyl groups containing 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5, and 6 carbon atoms). Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, and butyloxy. The alkoxy group can be substituted or unsubstituted.

[0237] The term "cycloalkenyl" refers to a partially unsaturated monocyclic or polycyclic ring of hydrocarbons, the cycloalkenyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like; polycyclic cycloalkenyl groups include spiro, fused, and bridged cycloalkenyl groups.

[0238] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring of hydrocarbons, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, or 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

[0239] The term "spirocycloalkyl" or when the cycloalkyl is spiro refers to a polycyclic group of 5 to 20 members, with each single ring sharing one carbon atom (termed a spiro atom) between rings in the system, which can contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g. 7, 8, 9 or 10 members). The spirocycloalkyl group can be classified as a mono-, bi- or polycycloalkyl group, preferably a mono- and bi- spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 5 or 5 / 6 mono- spirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0240] The term "fused cycloalkyl" or when the cycloalkyl is fused refers to a all-carbon polycyclic group of 5 to 20 members, with each ring sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings can contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g. 7, 8, 9 or 10 members). The fused cycloalkyl group can be classified as a bi-, tri-, tetra- or polycyclic fused cycloalkyl group, preferably a bi- or tri- cyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5 and 6 / 6 bi-cycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0241] The term "bridged cycloalkyl" or when the cycloalkyl is bridged refers to a all-carbon polycyclic group of 5 to 20 members, with any two rings sharing two carbon atoms not directly connected (i.e. sharing more than three), which can contain one or more double bonds. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g. 7, 8, 9 or 10 members). The bridged cycloalkyl group can be classified as a bi-, tri-, tetra- or polycyclic bridged cycloalkyl group, preferably a bi-, tri- or tetra-cyclic, more preferably a bi- or tri-cyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0242] The cycloalkyl ring includes cycloalkyl groups as described herein (including monocyclic, spiro, fused and bridged) fused to an aryl, heteroaryl or heterocyclyl ring, where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include etc; preferably The cycloalkyl group can be substituted or unsubstituted.

[0243] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ring-like substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone) or substituted by =NH, but not ring moieties of -O-O-, -O-S-, or -S-S-, with the remaining ring atoms being carbon. Preferably, there are 3 to 12 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) ring atoms, of which 1 to 5, e.g., 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, there are 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8), of which 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; more preferably, there are 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, there are 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused, and bridged heterocyclyl groups.

[0244] The term "spiroheterocyclyl" or when the heterocyclyl is spirocyclic, refers to a 5- to 20-membered, polycyclic heterocyclic group in which each single ring is shared with one atom (referred to as a spiro atom) in the system, one or more of which are heteroatoms selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It can contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). Spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bispiroheterocyclyl groups, depending on the number of spiro atoms shared between rings. More preferably, it is a 3 / 5-, 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6- membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl groups include:

[0245] The term "fused heterocyclyl" or when the heterocyclyl is fused, refers to a 5- to 20-membered, polycyclic heterocyclyl group in which each ring in the system shares a pair of adjacent atoms with another ring in the system, one or more of the rings can contain one or more double bonds, one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). It can be referred to as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 3- membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, and 6-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

[0246] The term "bridged heterocyclyl" or when the heterocyclyl is bridged, refers to a 5- to 14-membered, polycyclic heterocyclyl group in which any two rings share two non-adjacent atoms (i.e., share more than three atoms), which can contain one or more double bonds, one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7-, 8-, 9-, or 10-membered). It can be referred to as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

[0247] The heterocyclyl ring includes a heterocyclyl group as described herein (including monocyclic, spiro, fused, and bridged heterocyclyl) fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring that is attached to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0248] and the like. The heterocyclyl group can be substituted or unsubstituted.

[0249] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares a pair of adjacent carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described herein fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring that is attached to the parent structure is an aryl ring, non-limiting examples of which include: The aryl group can be substituted or unsubstituted.

[0250] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (e.g. 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5, 6, 7, 8, 9 or 10 membered), more preferably 5 membered or 6 membered, e.g. furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described herein, wherein the ring that is common to the parent structure is the heteroaryl ring, non-limiting examples of which include: Heteroaryl can be substituted or unsubstituted.

[0251] The terms "alkyl", "alkenyl", "alkynyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" and the like herein can be substituted or unsubstituted; when substituted, they can be substituted at any available attachment point with one or more of the same or different substituents, preferably independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0252] The above cycloalkyl, heterocyclyl, aryl and heteroaryl include a residue derived from removal of one hydrogen atom from a parent ring atom (e.g. ) or a residue derived from removal of two hydrogen atoms from the same or two different ring atoms of the parent, i.e. "divalent cycloalkyl", "divalent heterocyclyl", "arylene", "heteroarylene" (e.g. ) and can further include substituents on the same atom, or different atoms, directly connected to form a carbocyclic or heterocyclic ring;

[0253] For example in the present application, when R 5 is and is , it can be said that R j and R k together with the atom to which they are attached form a heterocyclic ring, and it can also be said that R j and R k together with the atom to which they are attached form a heterocyclyl group;

[0254] For another example, in the present application, when R 7 and R 5 together with the atom to which they are attached form (* indicates the site of attachment to T, and the dotted line indicates the bond common to ring A) it can be said that R 7 and R 5together with the atom to which it is attached form a heterocyclyl group, which can also be said to be R 7 and R 5 together with the atom to which it is attached form a heterocyclyl group.

[0255] The term "carbocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic ring, which can contain from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8).

[0256] The term "heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic ring, which can contain from 3 to 20 ring atoms, of which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which can optionally be oxidized (i.e., form a sulfoxide or sulfone), but does not include a ring moiety of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably, from 3 to 12 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) are contained, of which 1, 2, 3, 4, or 5 ring atoms are heteroatoms.

[0257] The term "cycloalkyloxy" means cycloalkyl-O-, wherein cycloalkyl is as defined herein.

[0258] The term "heterocyclyloxy" means heterocyclyl-O-, wherein heterocyclyl is as defined herein.

[0259] The term "cycloalkylthio" means cycloalkyl-S-, wherein cycloalkyl is as defined herein.

[0260] The term "heterocyclylthio" means heterocyclyl-S-, wherein heterocyclyl is as defined herein.

[0261] The term "haloalkyl" means an alkyl group substituted with one or more halogens, wherein halogen and alkyl are as defined herein.

[0262] The term "aminoalkyl" means an alkyl group substituted with one or more amino groups, wherein alkyl is as defined herein, e.g., -CH2NH2.

[0263] The term "cyanoalkyl" means an alkyl group substituted with one or more cyano groups, wherein alkyl is as defined herein, e.g., -CH2CN.

[0264] The term "haloalkoxy" means an alkoxy group substituted with one or more halogens, wherein halogen and alkoxy are as defined herein.

[0265] The term "halocycloalkyl" means a cycloalkyl group substituted with one or more halogens, wherein halogen and cycloalkyl are as defined herein.

[0266] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined herein.

[0267] The term "halogen" means F, CI, Br, or I.

[0268] The term "hydroxy" means -OH.

[0269] The term "amino" means -NH2.

[0270] The term "cyano" means -CN.

[0271] The term "nitro" means -NO2.

[0272] The term "oxo" or "keto" means "=O".

[0273] The term "carbonyl" means C=O.

[0274] The term "carboxyl" means -C(O)OH.

[0275] The term "carboxylate" means -C(O)O(alkyl), -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined herein.

[0276] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl can or can not be present, and that the description includes instances where the heterocyclyl is substituted with alkyl and instances where the heterocyclyl is not substituted with alkyl.

[0277] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3, of a group are independently of each other replaced with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, which can be determined (experimentally or theoretically) by a person skilled in the art without undue effort, as to whether a substitution is possible or not. For example, an amino or hydroxy group with a free hydrogen can not be stable when bound to a carbon atom with an unsaturated bond. DETAILED DESCRIPTION

[0278] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of the present application intended to be protected.

[0279] The raw materials and reagents used in the following examples are commercially available or can be prepared by known methods, unless otherwise specified.

[0280] The structure of the compounds is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is expressed in parts per million (ppm) relative to tetramethylsilane (TMS) as a standard, and the chemical shift is expressed in hertz (Hz). The NMR spectrum is recorded at room temperature on a Bruker Avance 400 spectrometer. -6ppm) units. NMR was measured by Bruker ASCEND TM -400 NMR spectrometer, the measuring solvent is deuterium dimethyl sulfoxide (DMSO-d6), deuterium chloroform (CDCl3), deuterium methanol (CD3OD), and the internal standard is tetramethylsilane (TMS). MS is measured by Agilent 6110, Agilent 1100, Agilent 6120, Agilent G6125B liquid chromatograph-mass spectrometer.

[0281] HPLC is measured by Shimadzu HPLC-2010C high pressure liquid chromatograph (XBRIDGE 2.1*50mm, 3.5um chromatographic column).

[0282] Chiral HPLC analysis is measured by THARSFC X5.

[0283] Thin layer chromatography silica gel plate uses Yantai Qingdao GF254 silica gel plate, and the silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.

[0284] Column chromatography generally uses Qingdao Marine silica gel 200-300 mesh silica gel as carrier.

[0285] High performance liquid preparation uses Waters 2767, Waters 2545, and innovative constant LC3000 preparative chromatograph.

[0286] Chiral preparative column chromatography uses Shimadzu LC-20AP, THARSFC PREP 80.

[0287] CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

[0288] Pressurized hydrogenation reaction uses Beijing Jiawei Kechuang Technology GCD-500G hydrogen generator.

[0289] Microwave reaction uses Biotage initiator+ microwave reactor.

[0290] Unless otherwise specified, the reactions in the experimental examples are carried out under argon atmosphere or nitrogen atmosphere.

[0291] Argon atmosphere or nitrogen atmosphere refers to that the reaction bottle is connected with an argon or nitrogen balloon with a volume of about 1 liter.

[0292] Hydrogen atmosphere refers to that the reaction bottle is connected with a hydrogen balloon with a volume of about 1 liter.

[0293] Unless otherwise specified, the reaction temperature in the experimental examples is room temperature, and the temperature range is 20-30°C.

[0294] The skilled person in the art should understand that the chiral compounds split can be distinguished by the order of retention time in the chiral chromatographic column, therefore, the chiral compounds split according to the order of retention time are distinguished by the number suffix P1, P2, etc. That is, for example, the suffix P1 corresponds to the chiral compound with a certain chiral structure eluted out of the chiral chromatographic column earlier, and the suffix P2 corresponds to the chiral compound with a certain chiral structure eluted out of the chiral chromatographic column later. If the absolute configuration of the compound is listed in the structural formula, it does not mean that it directly corresponds to the compound with the number suffix P1, P2, but only indicates the two existing forms of absolute configuration. The absolute configuration of the compound with the number suffix P1, P2 is based on the objective corresponding absolute configuration marked by the specific retention time.

[0295] The reagent English abbreviation corresponds to the reagent name:

[0296] Example 1 (compound 1)

[0297] First step: synthesis of compound 1b

[0298] Sodium hydride (0.34 g, 8.51 mmol) was slowly added to a mixture of trimethylsulfoxonium iodide (1.88 g, 8.51 mmol) in tetrahydrofuran and dimethyl sulfoxide (20 mL / 20 mL) at 0°C. After stirring the mixture at room temperature for 1 hour, a solution of compound 1a (2 g, 5.49 mmol, synthesis method reference patent CN116782894A, page 50-51, paragraph 0349-0354, synthesis of example 4) in tetrahydrofuran (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction liquid was poured into ice water (50 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 1b (1.70 g, crude), which was used directly in the next step without purification.

[0299] Second step: synthesis of compound 1c

[0300] To a solution of compound 1b (1.70 g, 4.49 mmol) in methanol, tetrahydrofuran and water (6 mL / 6 mL / 6 mL) was added zinc powder (1.47 g, 22.47 mmol) and ammonium chloride (2.41 g, 44.94 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Biotage-Flash 4l4® (column: C18 reverse phase column, acetonitrile-water (0.1% ammonia water); gradient: 60%-70%) to give compound 1c (180 mg). MS m / z (ESI): 348.0 [M+1] + .

[0301] Third Step: Synthesis of compound 1f

[0302] To a solution of compound 1d (105.5 mg, 0.49 mmol, synthesis method refer to patent CN102317291A, page 104, paragraph 1394-1395, method B, first step of intermediate example 44) in 1,4-dioxane (0.5 mL) was added trimethyl orthoformate (77.6 mg, 0.73 mmol) at room temperature. The reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature. To the mixture was added a solution of compound 1c (170 mg, 0.49 mmol) and acetic acid (29.3 mg, 0.49 mmol) in 1,4-dioxane (0.5 mL). The reaction mixture was stirred at 120 °C for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 1f (200 mg, crude). The crude was used directly in the next step without purification. MS m / z (ESI): 555.4 [M+1] + .

[0303] Fourth Step: Synthesis of compound 1

[0304] To a solution of compound 1f (200 mg, 0.36 mmol) in 1,4-dioxane was added a solution of HC1 in 1,4-dioxane (4.0 M, 0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 1 (5.50 mg). MS m / z (ESI): 325.0 [M+1] + .1 H NMR (400 MHz, DMSO-d6) d 8.62 (d, J = 3.2 Hz, 1H), 7.39 - 7.34 (m, 1H), 6.92 - 6.86 (m, 1H), 4.58 - 4.10 (m, 6H), 3.76 - 3.69 (m, 1H), 1.70 - 1.61 (m, 1H), 1.51 - 1.42 (m, 1H).

[0305] Example 2 (Compound 1-P1 and 1-P2)

[0306] First Step: Synthesis of Compound 1g-P1 and 1g-P2

[0307] Di-tert-butyl dicarbonate (181.2 mg, 0.83 mmol) was added to a solution of potassium carbonate (114.8 mg, 0.83 mmol) and compound 1 (90 mg, 0.28 mmol) in tetrahydrofuran (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, and the residue was separated by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IH SFC, 20*250 mm; flow rate: 38 mL / min column temperature: room temperature; mobile phase: A: carbon dioxide B: methanol) to give compound 1g-P1 (30 mg) and compound 1g-P2 (30 mg).

[0308] Compound 1g-P1: MS m / z (ESI): 525.35 [M+1] + . Supercritical fluid chromatography SFC: Retention time 1.988 min, UV = 214 nm.

[0309] Compound 1g-P2: MS m / z (ESI): 525.35 [M+1] + . Supercritical fluid chromatography SFC: Retention time 2.257 min, UV = 214 nm.

[0310] Second Step: Synthesis of Compound 1-P1 and 1-P2

[0311] HCl in 1,4-dioxane (4.0 M, 0.5 mL) was added to a solution of compound 1g-P1 (30 mg, 0.070 mmol) in 1,4-dioxane (0.5 mL) at room temperature. The reaction mixture was stirred in a sealed tube at room temperature for 1 h. The reaction was purified by high performance liquid preparation chromatography (column: Xbridge-C18; 19 x 150 mm, 5 µm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 1-P1 (11.5 mg). MS m / z (ESI): 325.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.33 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.45 – 4.29 (m, 1H), 4.19 – 4.08 (m, 2H), 4.06 – 3.92 (m, 2H), 3.76 – 3.68 (m, 1H), 2.46 – 2.37 (m, 1H), 1.72 – 1.60 (m, 1H), 1.54 – 1.40 (m, 1H).

[0312] HCl in 1,4-dioxane (4.0 M, 0.5 mL) was added to a solution of compound 1g-P2 (30 mg, 0.070 mmol) in 1,4-dioxane (0.5 mL) at room temperature. The reaction mixture was stirred in a sealed tube at room temperature for 1 h. The reaction was purified by high performance liquid preparation chromatography (column: Xbridge-C18; 19 x 150 mm, 5 µm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 1-P2 (12.0 mg). MS m / z (ESI): 325.00 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1H), 8.33 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.45 – 4.29 (m, 1H), 4.19 – 4.08 (m, 2H), 4.06 – 3.92 (m, 2H), 3.76 – 3.68 (m, 1H), 2.46 – 2.37 (m, 1H), 1.72 – 1.60 (m, 1H), 1.54 – 1.40 (m, 1H).

[0313] Example 3 (compounds 8-P1 and 8-P2)

[0314] First Step: Synthesis of compound 8b-P1 and 8b-P2

[0315] Trimethyl orthoformate (434.4 mg, 4.09 mmol) was added to a solution of compound 8a (500 mg, 2.05 mmol, synthesis method refer to WO2018037223 A1 page P148 synthesis of intermediate 123) in 1,4-dioxane (1 mL) at room temperature, the reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature, a solution of compound 1c (712.9 mg, 4.09 mmol) and acetic acid (122.9 mg, 2.05 mmol) in 1,4-dioxane (3.5 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 8b (150 mg). Compound 8b (150 mg) was resolved by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IH SFC 20mm I.D.*250mmL, 5μm; mobile phase: A: CO2 B: MeOH [0.1% NH3(7M solution in MeOH)]; flow rate: 38ml / min] to obtain compound 8b-P1 (45 mg) and compound 8b-P2 (50 mg).

[0316] Compound 8b-P1: MS m / z (ESI): 583.3 [M+1] + Supercritical fluid chromatography SFC: retention time 4.288 min, UV = 214 nm.

[0317] Compound 8b-P2: MS m / z (ESI): 583.3 [M+1] + Supercritical fluid chromatography SFC: retention time 5.386 min, UV = 214 nm.

[0318] Second Step: Synthesis of compound 8-P1 and 8-P2

[0319] A solution of HCl in 1,4-dioxane (4.0 M, 2 mL) was added to compound 8b-P1 (45 mg, 0.086 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was lyophilized to obtain compound 8-P1 (35.7 mg). MS m / z (ESI): 353.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.29 - 8.89 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.97 - 6.86 (m, 1H), 3.95 - 3.83 (m, 1H), 3.54 - 3.45 (m, 1H), 3.45 - 3.34 (m, 2H), 3.12 - 2.95 (m, 2H), 2.66 - 2.59 (m, 1H), 2.21 - 2.11 (m, 2H), 2.02 - 1.91 (m, 2H), 1.86 - 1.76 (m, 1H), 1.61 - 1.50 (m, 1H).

[0320] A solution of HCl in 1,4-dioxane (4.0 M, 2 mL) was added to compound 8b-P2 (50 mg, 0.086 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was lyophilized to obtain compound 8-P2 (18.6 mg). MS m / z (ESI): 353.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.29 - 8.89 (m, 1H), 7.40 (d, J = 8.8 Hz, 1H), 6.97 - 6.86 (m, 1H), 3.95 - 3.83 (m, 1H), 3.54 - 3.45 (m, 1H), 3.45 - 3.34 (m, 2H), 3.12 - 2.95 (m, 2H), 2.66 - 2.59 (m, 1H), 2.21 - 2.11 (m, 2H), 2.02 - 1.91 (m, 2H), 1.86 - 1.76 (m, 1H), 1.61 - 1.50 (m, 1H).

[0321] Example 4 (compounds 11-1-P1, 11-1-P2, 11-2-P1, 11-2-P2)

[0322] First step: synthesis of compound 11b-1

[0323] Trimethylorthoformate (65.8 mg, 0.62 mmol) was added to a solution of compound 11a-1 (40.0 mg, 0.31 mmol (for synthesis, refer to patent US20190308969 A1 page P196 synthesis of compound 38.2) in 1,4-dioxane (1.0 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. Then cooled to room temperature, a solution of compound 1c (107.6 mg, 0.31 mmol) and acetic acid (18.6 mg, 0.31 mmol) in 1,4-dioxane (1.0 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 11b-1 (25 mg). MS m / z (ESI): 470.05 [M+1] + .

[0324] Second step: synthesis of compound 11-1, 11-1-P1 and 11-1-P2

[0325] Compound 11b-1 (25 mg, 0.053 mmol) was added to a solution of HCl in 1,4-dioxane (2.0 M, 2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was freeze-dried to give compound 11-1 (20.0 mg). MS m / z (ESI): 339.95 [M+1] + Compound 11-1 (25 mg) was purified by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IC-10SFC 30 mm I.D.*250 mm L, 10 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3(7M solution in MeOH)]; flow rate: 100 ml / min] to give compound 11-1-P1 (4.39 mg) and compound 11-1-P2 (3.02 mg).

[0326] Compound 11-1-P1: MS m / z (ESI): 340.05 [M+1] + . Super critical fluid chromatography SFC: retention time 4.304 min, UV = 214 nm. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.54 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.08 (t, J = 7.8 Hz, 1H), 3.89 - 3.69 (m, 5H), 2.38 - 2.15 (m, 3H), 1.76 - 1.66 (m, 1H), 1.58 - 1.49 (m, 1H).

[0327] Compound 11-1-P2: MS m / z (ESI): 340.00 [M+1] + . Supercritical fluid chromatography SFC: Retention time 5.368 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.54 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.08 (t, J = 7.8 Hz, 1H), 3.89 - 3.69 (m, 5H), 2.38 - 2.15 (m, 3H), 1.76 - 1.66 (m, 1H), 1.58 - 1.49 (m, 1H).

[0328] Third step: synthesis of compound 11b-2

[0329] Trimethyl orthoformate (60.8 mg, 0.57 mmol) was added to a solution of compound 11a-2 (37.3 mg, 0.28 mmol (synthesis method refer to US20190308969 A1 specification P196 compound 38.2 synthesis)) in 1,4-dioxane (1.0 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour. Then cooled to room temperature, to the mixture was added a solution of compound 1c (100.0 mg, 0.28 mmol) and acetic acid (17.2 mg, 0.28 mmol) in 1,4-dioxane (1.0 mL), and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 11b-2 (50 mg). MS m / z (ESI): 470.25 [M+1] + .

[0330] Fourth step: synthesis of compounds 11-2, 11-2-P1 and 11-2-P2

[0331] Compound 11b-2 (50 mg, 0.11 mmol) was dissolved in HCl in 1,4-dioxane (2.0 M, 2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Xbridge-C18; 19 x 150 mm, 5 μm; mobile phase: acetonitrile-water (0.05% ammonia water); gradient: 20-30%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 11-2 (10 mg). MS m / z (ESI): 339.80 [M+1] + Compound 11-2 (10 mg) was resolved by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IC-10 SFC 30 mm I.D.*250 mm L, 10 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3(7M solution in MeOH)]; flow rate: 100 ml / min] to obtain compound 11-2-P1 (1.94 mg) and compound 11-2-P2 (2.24 mg).

[0332] Compound 11-2-P1: MS m / z (ESI): 340.15 [M+1] + Super critical fluid chromatography SFC: retention time 3.093 min, UV = 214 nm.

[0333] Compound 11-2-P2: MS m / z (ESI): 340.10 [M+1] + Super critical fluid chromatography SFC: retention time 3.477 min, UV = 214 nm.

[0334] Example 5 (compounds 12-1-P1, 12-1-P2, 12-2-P1, 12-2-P2)

[0335] First step: synthesis of compounds 12b-1, 12b-1-P1 and 12b-1-P2

[0336] Trifluoroformic acid trimethyl ester (137.1 mg, 1.29 mmol) was added to a solution of compound 12a-1 (218.1 mg, 0.95 mmol, synthesis method refer to synthesis of intermediate 2 in CN117946111A page 109) in 1,4-dioxane (0.5 mL) at room temperature, the reaction mixture was stirred at 45 °C for 1 h. Then cooled to room temperature, a solution of compound 1c (300 mg, 0.86 mmol) and acetic acid (51.7 mg, 0.86 mmol) in 1,4-dioxane (2.5 mL) was added to the mixture, the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound 12b-1 (150 mg). Compound 12b-1 (150 mg) was purified by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IH SFC 20 mm I.D. * 250 mm L, 5 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3(7M solution in MeOH)]; flow rate: 38 ml / min] to give compound 12b-1-P1 (50 mg) and compound 12b-1-P2 (50 mg).

[0337] Compound 12b-1-P1: MS m / z (ESI): 569.3 [M+1] + Supercritical fluid chromatography SFC: Retention time 2.590 min, UV = 214 nm.

[0338] Compound 12b-1-P2: MS m / z (ESI): 569.3 [M+1] + Supercritical fluid chromatography SFC: Retention time 2.957 min, UV = 214 nm.

[0339] Second step: synthesis of compound 12-1-P1 and 12-1-P2

[0340] HCl in 1,4-dioxane (4.0 M, 2 mL) was added to compound 12b-1-P1 (50 mg, 0.087 mmol) at room temperature, the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was freeze-dried to give compound 12-1-P1 (33.6 mg). MS m / z (ESI): 339.1 [M+1] +Supercritical fluid chromatography SFC: Retention time = 2.102 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 - 8.73 (m, 1H), 7.39 (dd, J = 8.8, 1.6 Hz, 1H), 6.89 (dd, J = 8.8, 2.4 Hz, 1H), 3.97 - 3.89 (m, 1H), 3.85 - 3.79 (m, 1H), 3.60 - 3.47 (m, 3H), 3.39 - 3.29 (m, 2H), 2.45 - 2.38 (m, 1H), 2.20 - 2.09 (m, 1H), 2.04 - 1.93 (m, 1H), 1.77 (d, 1H), 1.63 - 1.52 (m, 1H).

[0341] A solution of HC1 in 1,4-dioxane (4.0 M, 2 mL) was added to compound 12b-1-P2 (50 mg, 0.087 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was lyophilized to obtain compound 12-1-P2 (31.9 mg). MS m / z (ESI): 339.1 [M+1] + Supercritical fluid chromatography SFC: Retention time = 2.363 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.76 (m, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.04 - 3.94 (m, 1H), 3.65 - 3.59 (m, 3H), 3.56 - 3.49 (m, 1H), 3.40 - 3.27 (m, 2H), 2.63 - 2.59 (m, 1H), 2.47 - 2.38 (m, 1H), 2.25 - 2.11 (m, 1H), 1.83 - 1.72 (m, 1H), 1.59 - 1.51 (m, 1H).

[0342] Third step: synthesis of compounds 12b-2, 12b-2-P1 and 12b-2-P2

[0343] Trimethyl orthoformate (182.8 mg, 1.72 mmol) was added to a solution of compound 12a-2 (290.9 mg, 1.26 mmol, synthesis method refer to the synthesis of intermediate 2 in the specification of patent CN117946111A, page 109) in 1,4-dioxane (2.0 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. Then cooled to room temperature, a solution of compound 1c (400 mg, 1.14 mmol) and acetic acid (68.9 mg, 1.14 mmol) in 1,4-dioxane (4.0 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE / EA = 1 / 0 ~ 1 / 1) to obtain compound 12b-2 (300 mg). Compound 12b-2 (300 mg) was resolved by supercritical fluid chiral chromatography [equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak IH SFC 20 mm I.D. * 250 mm L, 5 μm; mobile phase: A: CO2 B: MeOH [0.1% NH3(7M solution in MeOH)]; flow rate: 38 ml / min] to obtain compound 12b-2-P1 (130 mg) and compound 12b-2-P2 (130 mg).

[0344] Compound 12b-2-P1: MS m / z (ESI): 569.1 [M+1] + Supercritical fluid chromatography SFC: retention time 2.579 min, UV = 214 nm.

[0345] Compound 12b-2-P2: MS m / z (ESI): 569.1 [M+1] + Supercritical fluid chromatography SFC: retention time 3.343 min, UV = 214 nm.

[0346] Fourth step: synthesis of compound 12-2-P1 and 12-2-P2

[0347] HCl solution in 1,4-dioxane (4.0 M, 2 mL) was added to compound 12b-2-P1 (130 mg, 0.23 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was freeze-dried to obtain compound 12-2-P1 (53.8 mg). MS m / z (ESI): 339.0 [M+1] + Supercritical fluid chromatography SFC: retention time = 2.165 min, UV = 214 nm. 1H NMR (400 MHz, CD3OD) δ 9.83 (s, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.40 - 4.29 (m, 1H), 4.22 - 4.13 (m, 1H), 3.88 - 3.79 (m, 1H), 3.78 - 3.68 (m, 1H), 3.65 - 3.45 (m, 2H), 2.85 - 2.73 (m, 1H), 2.69 - 2.58 (m, 1H), 2.49 - 2.36 (m, 1H), 2.04 - 1.92 (m, 1H), 1.85 - 1.69 (m, 1H).

[0348] A solution of HC1 in 1,4-dioxane (4.0 M, 2 mL) was added to compound 12b-2-P2 (130 mg, 0.23 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was lyophilized to obtain compound 12-2-P2 (58.5 mg). MS m / z (ESI): 339.0 [M+1] + Supercritical fluid chromatography SFC: Retention time = 2.201 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 3.97 (p, 1H), 3.92 - 3.84 (m, 1H), 3.66 - 3.61 (m, 1H), 3.59 - 3.51 (m, 1H), 3.42 - 3.26 (m, 2H), 2.67 - 2.60 (m, 1H), 2.49 - 2.38 (m, 1H), 2.25 - 2.09 (m, 1H), 1.90 - 1.69 (m, 1H), 1.68 - 1.51 (m, 1H).

[0349] Example 6 (compound 23)

[0350] First step: synthesis of compound 23c

[0351] Sodium hydride (8.19 g, 204.84 mmol) was added to a solution of compound 23c (40.18 g, 204.84 mmol) in tetrahydrofuran (300 mL) at 0 °C. After the mixture was stirred for 30 min, a solution of compound 23a (35 g, 170.70 mmol) (synthesis method, refer to patent WO2016123164A1, page 51, example 36, step A) in tetrahydrofuran (200 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1.5 h. After the reaction was completed, the reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (1000 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 23c (36 g). MS m / z (ESI): 275.00 [M+1] + .

[0352] Second step: synthesis of compound 23d

[0353] A solution of diazomethane in ether (727.0 mL, 436.20 mmol) was slowly added dropwise to a solution of compound 23c (20 g, 72.70 mmol) and palladium acetate (0.98 g, 4.36 mmol) in tetrahydrofuran (200 mL) at -20 °C. The reaction mixture was stirred at room temperature for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 23d (20 g). The crude product was used directly in the next step without purification. MS m / z (ESI): 288.95 [M+1] + .

[0354] Third step: synthesis of compound 23e

[0355] Sodium hydroxide (13.84 g, 346.00 mmol) was added to a solution of compound 23d (80 g, 276.70 mmol) in a mixture of methanol / water (600 mL / 200 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was adjusted to pH = 4 with dilute hydrochloric acid (1000 mL, 2N), extracted with ethyl acetate (200 mL x 2), and the combined organic phase was washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1%-10%) to give compound 23e (70 g). MS m / z (ESI): 259.05 [M-1] - .

[0356] Fourth step: synthesis of compound 23f

[0357] Compound 23d (70 g, 0.27 mol) and triethylamine (35.27 g, 0.35 mol) in tert-butanol (700 mL) under nitrogen protection, the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1%-30%) to obtain compound 23f (70 g). MS m / z (ESI): 276.10 [M-55] + .

[0358] Step 5: Synthesis of compound 23g

[0359] Boron tribromide (18.91 g, 75.50 mmol) was added to a solution of compound 23f (5 g, 15.10 mmol) in dichloromethane (100 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1%-20%) to obtain compound 23g (2 g). MS m / z (ESI): 218.05 [M+1] + .

[0360] Step 6: Synthesis of compound 23

[0361] Trimethyl orthoformate (97.2 mg, 0.91 mmol) was added to a solution of compound 23h (89.5 mg, 0.68 mmol) (synthesis method reference WO2023158626A1 page 91 intermediate 1 step 7) in 1,4-dioxane (1.0 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour. Then cooled to room temperature, a solution of compound 23g (50.0 mg, 0.22 mmol) and acetic acid (13.7 mg, 0.22 mmol) in 1,4-dioxane (1.0 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 23 (1.81 mg). MS m / z (ESI): 340.05 [M+1] + .

[0362] Example 7 (compound 113)

[0363] Step 1: Synthesis of compound 113a

[0364] Compound 23f (14 g, 42.10 mmol) was dissolved in HCl in 1,4-dioxane (70 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 113a (crude, 9 g), which was used directly in the next step without purification. MS m / z (ESI): 232.05 [M+1] + .

[0365] Second Step: Synthesis of compound 113c

[0366] Hydrazine hydrate (559.3 mg, 11.17 mmol) was added to a solution of compound 113b (400 mg, 2.79 mmol) in ethanol (8 mL) at room temperature, and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 to 3 / 1) to obtain compound 113c (300 mg). MS m / z (ESI): 143.90 [M+1] + .

[0367] Third Step: Synthesis of compound 113d

[0368] Trimethyl orthoformate (296.1 mg, 2.79 mmol) was added to a solution of compound 113c (200 mg, 1.39 mmol) in 1,4-dioxane (4 mL) at room temperature, and the reaction mixture was stirred at 45°C for 1 hour, and then cooled to room temperature. A solution of compound 113a (324.21 mg, 1.39 mmol) and acetic acid (83.88 mg, 1.39 mmol) in 1,4-dioxane (1 mL) was added to the mixture, and the reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction solution was quenched with saturated sodium bicarbonate (5 mL), extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to obtain compound 113d (200 mg). MS m / z (ESI): 367.10 [M+1] + .

[0369] Fourth Step: Synthesis of compound 113e

[0370] Sodium bicarbonate (411.7 mg, 4.90 mmol) and iodine (932.9 mg, 3.67 mmol) were added to a solution of compound 113d (180 mg, 0.49 mmol) in tetrahydrofuran and water (3.6 mL / 1.2 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was quenched with saturated sodium thiosulfate solution (5 mL), extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography on silica gel plate (DCM / MeOH = 10 / 1) to give compound 113e (30 mg). MS m / z (ESI): 380.80 [M+1] + .

[0371] Fifth step: synthesis of compound 113

[0372] Boron tribromide (328.4 mg, 1.31 mmol) was slowly added dropwise to a solution of compound 113e (50 mg, 0.13 mmol) in dichloromethane (2 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 113 (8 mg). MS m / z (ESI): 367.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.57 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.02-3.91 (m, 1H), 3.83-3.72 (m, 2H), 3.70-3.62 (m, 1H), 2.75 (d, J = 5.2 Hz, 3H), 2.72-2.56 (m, 3H), 1.80-1.68 (m, 1H), 1.56-1.46 (m, 1H).

[0373] Example 8 (compound 135)

[0374] First step: synthesis of compound 135b

[0375] Compound 135a (1.00 g, 3.30 mmol) (for the synthesis method, refer to patent WO2021071821 A1, page 61, example 4, step d), tris(dibenzylideneacetone)dipalladium (151.1 mg, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (96.5 mg, 0.17 mmol) and cesium carbonate (3.22 g, 9.90 mmol) were added to a solution of cyclopentanone (555.3 mg, 6.60 mmol) in 1,4-dioxane (20 mL) under nitrogen protection, and the reaction mixture was stirred at 100 °C for 12 h. After the reaction was completed, it was extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 1 / 0 ~ 9 / 1) to give compound 135b (400 mg). MS m / z (ESI): 259.0 [M+1] + .

[0376] Second step: synthesis of compound 135c

[0377] Hydroxylamine hydrochloride (214.5 mg, 3.09 mmol) and sodium acetate (379.7 mg, 4.63 mmol) were added to a solution of compound 135b (400 mg, 1.54 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 5 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give compound 135c (400 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 273.9 [M+1] + .

[0378] Third step: synthesis of compound 135d

[0379] Raney nickel (77.1 mg, 1.31 mmol) was added to a solution of compound 135c (180 mg, 0.66 mmol) in methanol, and the reaction mixture was stirred at room temperature under hydrogen atmosphere for 2 h. After the reaction was completed, it was extracted with ethyl acetate (20 mL), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 9 / 1) to give compound 135d (80 mg). MS m / z (ESI): 260.0 [M+1] + .

[0380] Fourth step: synthesis of compound 135e

[0381] Boron tribromide (385.2 mg, 1.54 mmol) was added to a dichloromethane (5 mL) solution of compound 135d (80 mg, 0.31 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0–5 / 1) to give compound 135e (40 mg). MS m / z (ESI): 245.9 [M+1] + .

[0382] Step 5: Synthesis of Compound 135

[0383] At room temperature, trimethyl orthoformate (34.5 mg, 0.32 mmol) was added to a 2 mL solution of 1,4-dioxane (2 mL) of compound 135f (42.3 mg, 0.32 mmol) (synthetic method referred to in US20190308969 A1, page 196, synthesis of compound 38.2). The reaction mixture was stirred at 45°C for 1 hour. Then, a 0.5 mL solution of 1,4-dioxane (40 mg, 0.16 mmol) of compound 135e and acetic acid (19.5 mg, 0.32 mmol) was added. The reaction mixture was stirred at 120°C for 16 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate (10 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to preparative high-performance liquid chromatography (HPLC) (column: Gemini 5 μm C). 18 The column was purified to obtain compound 135 (5.7 mg) using a 150*21.2 mm column (150 x 21.2 mm); mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar). MS m / z (ESI): 368.0 [M+1] + . 1 H NMR(400MHz, DMSO-d6)10.13(s,1H),8.33(d,J=4.0Hz,1H),7.21(dd,J=8.8 ,3.2Hz,1H),6.62(dd,J=8.8,3.2Hz,1H),4.94–4.77(m,1H),4.06–4.00(m,1 H),3.84–3.68(m,2H),3.47–3.36(m,1H),3.14(p,J=8.8Hz,1H),2.73(dd,J =15.6,7.2Hz,1H),2.42–2.24(m,3H),2.19–2.08(m,1H),1.98–1.50(m,4H).

[0384] Example 9 (Compound 169)

[0385] First Step: Synthesis of compound 169a

[0386] Bromine (879.4 mg, 5.50 mmol) was added to a solution of compound 23g (1000 mg, 4.58 mmol) in acetic acid (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 169a (600 mg). MS m / z (ESI): 296.0 [M+1] + .

[0387] Second Step: Synthesis of compound 169b

[0388] Trimethyl orthoformate (482.4 mg, 4.55 mmol) was added to a solution of compound 135f (394.4 mg, 3.03 mmol) in 1,4-dioxane (10 mL) at room temperature. The reaction mixture was stirred at 45°C for 1 hour. To the mixture was added a solution of compound 169a (300 mg, 1.01 mmol) and acetic acid (121.3 mg, 2.02 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, extraction was performed with ethyl acetate (100 mL x 3), and the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 9 / 1) to obtain compound 169b (150 mg). MS m / z (ESI): 418.1 [M+1] + .

[0389] Third Step: Synthesis of compound 169

[0390] Potassium cyanide (78.6 mg, 0.24 mmol), palladium acetate (1.1 mg, 0.0048 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (1.9 mg, 0.0048 mmol) were added to a mixture of compound 169b (10 mg, 0.024 mmol) in n-butanol and water (1 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 100°C for 12 hours. Ten batches were prepared in parallel, and after the reaction was completed, the ten batches of reaction solutions (a total of 100 mg of compound 169b) were combined and filtered. The filter cake was washed with methanol (5 mL x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography (preparative column: Gemini 5um C 18150*21.2 mm; mobile phase: acetonitrile-water (0.05% ammonia water); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 169 (0.78 mg). MS m / z (ESI): 364.9 [M+1] + .

[0391] Example 10 (compound 168)

[0392] First step: synthesis of compound 168b

[0393] Trimethyl orthoformate (964.8 mg, 9.09 mmol) was added to a solution of compound 168a (1395.8 mg, 6.06 mmol) in 1,4-dioxane (10 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. To the mixture was added a solution of compound 169a (600 mg, 2.02 mmol) and acetic acid (121.3 mg, 2.02 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction, extraction was performed with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 9 / 1) to give compound 168b (280 mg). MS m / z (ESI): 516.90 [M+1] + .

[0394] Second step: synthesis of compound 168c

[0395] Potassium ferrocyanide (44.2 mg, 0.13 mmol), palladium acetate (10.8 mg, 0.048 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl biphenyl (13.7 mg, 0.029 mmol) were added to a mixture of compound 168b (5 mg, 0.0096 mmol) in n-butanol and water (1 mL / 1 mL) at room temperature, and the reaction mixture was stirred at 100 °C for 12 h. Ten batches were prepared in parallel, and after completion of the reaction, the ten batches (total 50 mg of compound 168b) were combined and filtered. The filter cake was washed with methanol (5 mL x 3), and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by high-performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% ammonia water); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 168c (6 mg in total from ten batches). MS m / z (ESI): 464.1 [M+1]+ .

[0396] Step 3: Synthesis of compound 168

[0397] To a solution of compound 168c (6 mg, 0.013 mmol) in 1,4-dioxane (1 mL) was added hydrochloric acid-1,4-dioxane solution (4.0 M, 2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 168 (5 mg). MS m / z (ESI): 363.9 [M+1] + .

[0398] Example 11 (compound 105)

[0399] Step 1: Synthesis of compound 105b

[0400] To a solution of compound 105a (synthesis method refer to patent WO2018233633A1 specification page 83 synthesis of compound WX083-2) in 1,4-dioxane (1 mL) was added trimethyl orthoformate (18.2 mg, 0.17 mmol) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. After the reaction was completed, acetic acid (8.6 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the reaction mixture, and the reaction mixture was raised to 120 °C and stirred for 15 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to give compound 105b (35 mg). MS m / z (ESI): 456.3 [M+1] + .

[0401] Step 2: Synthesis of compound 105

[0402] To a solution of compound 105b (30 mg, 0.06 mmol) in dichloromethane (1.5 mL) was added trifluoroacetic acid (0.5 mL) at room temperature, and the reaction mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was adjusted to pH = 8 with ammonia water, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 105 (11.9 mg). MS m / z (ESI): 326.10 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.57 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.95 - 4.84 (m, 4H), 4.68 - 4.59 (m, 1H), 3.69 - 3.62 (m, 1H), 2.46 - 2.42 (m, 1H), 1.64 - 1.56 (m, 1H), 1.44 (dd, J = 13.6, 6.8 Hz, 1H).

[0403] Example 12 (Compound 114)

[0404] First Step: Synthesis of compound 114b

[0405] Hydrazine hydrate (342.3 mg, 5.47 mmol) was added to a solution of compound 114a (400 mg, 2.74 mmol) in ethanol (3 mL), the reaction mixture was stirred at 80 °C for 6 h. The reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 0%-10%) to give compound 114b (300 mg). MS m / z (ESI): 146.8 [M+1] + .

[0406] Second Step: Synthesis of compound 114c

[0407] Trimethyl orthoformate (76.2 mg, 0.72 mmol) was added to a solution of compound 114b (70 mg, 0.48 mmol) in 1,4-dioxane (1 mL) at room temperature, the reaction mixture was stirred at 45 °C for 1 h, then cooled to room temperature, a solution of 113a (111.1 mg, 0.48 mmol) and acetic acid (28.7 mg, 0.48 mmol) in 1,4-dioxane (1 mL) was added to the mixture, the reaction mixture was stirred at 120 °C for 16 h. The reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1%-15%) to give compound 114c (80 mg). MS m / z (ESI): 370.21 [M+1] + .

[0408] Third Step: Synthesis of compound 114d

[0409] To a solution of compound 114c (80 mg, 0.22 mmol) in dichloromethane (2 mL) was added 3-chloroperbenzoic acid (111.8 mg, 0.065 mmol), and the reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1% - 10%) to give compound 114d (65 mg). MS m / z (ESI): 402.15 [M+1] + .

[0410] Fourth Step: Synthesis of compound 114

[0411] To a solution of compound 114d (50 mg, 0.12 mmol) in dichloromethane (5 mL) was added boron tribromide (1.0 M in dichloromethane, 1 mL, 1.24 mmol), and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min) to give compound 114 (12.8 mg). MS m / z (ESI): 388.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.19 - 4.01 (m, 1H), 3.88 - 3.77 (m, 1H), 3.69 - 3.55 (m, 1H), 3.45 - 3.36 (m, 2H), 3.25 - 3.11 (m, 1H), 2.70 - 2.54 (m, 2H), 2.41 - 2.30 (m, 1H), 1.81 - 1.71 (m, 1H), 1.53 - 1.44 (m, 1H).

[0412] Example 13 (compound 126)

[0413] First Step: Synthesis of compound 126a

[0414] Compound 126a (170 mg) was obtained from compound 135f (336.4 mg, 2.58 mmol) following the same procedure as described in Example 1, Step 2. MS m / z (ESI): 353.6 [M+1] + .

[0415] Second Step: Synthesis of compound 126b

[0416] Compound 126b (30 mg) was obtained from compound 126a (150.0 mg, 0.42 mmol) following the same procedure as described in Example 1, Step 2. MS m / z (ESI): 390.0 [M+1] + .

[0417] Third Step: Synthesis of compound 126

[0418] Compound 126 (3.0 mg) was obtained from compound 126b (30 mg) following the same procedure as described in Example 1, Step 3. MS m / z (ESI): 373.9 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 7.32 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.12 - 3.96 (m, 1H), 3.90 - 3.83 (m, 2H), 3.80 - 3.75 (m, 2H), 2.80 - 2.77 (m, 1H), 2.30 - 2.18 (m, 2H), 1.97 - 1.86 (m, 1H), 1.74 - 1.66 (m, 1H).

[0419] Example 14 (Compound 133)

[0420] First Step: Synthesis of compound 133a

[0421] Compound 1c (120 mg, 0.34 mmol) was dissolved in 1,4-dioxane (5 mL), and compound 168a (93.55 mg, 0.41 mmol), trimethyl orthoformate (0.043 g, 0.41 mmol) and acetic acid (0.20 g, 0.34 mmol) were added successively. The reaction mixture was stirred at 120 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0-10%) to obtain compound 133a (60 mg). MS m / z (ESI): 569.2 [M+1] + .

[0422] Second Step: Synthesis of compound 133b

[0423] Compound 133a (60 mg, 0.11 mmol) was dissolved in acetonitrile (2 mL), and NBS (23.49 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL) and extracted with EA (10 mL x 3), the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0-10%) to obtain compound 133b (50 mg). MS m / z (ESI): 647.4 [M+1] + .

[0424] Third Step: Synthesis of compound 133

[0425] Compound 133b (50 mg, 0.077 mmol) was dissolved in hydrochloric acid 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min) to obtain compound 133 (6.57 mg). MS m / z (ESI): 418.9 [M+1] + .

[0426] Example 15 (Compound 153)

[0427] First Step: Synthesis of compound 153b

[0428] Hydrazine hydrate (372.3 mg, 6.32 mmol) was added to a solution of compound 153a (500 mg, 3.16 mmol) in ethanol (10 ml) at room temperature, and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to obtain compound 153b (140 mg). MS m / z (ESI): 159.1 [M+1] + .

[0429] Second Step: Synthesis of compound 153

[0430] Trimethyl orthoformate (102.2 mg, 0.96 mmol) was added to a solution of compound 153b (108.8 mg, 0.69 mmol) in 1,4-dioxane (1 ml) at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour. After the reaction was completed, acetic acid (16.5 mg, 0.28 mmol) and compound 23g (60 mg, 0.28 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 120 °C for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 153 (9.8 mg). MS m / z (ESI): 368.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.83 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.01 - 3.92 (m, 1H), 3.50 - 3.39 (m, 1H), 3.08 - 2.92 (m, 1H), 2.64 - 2.56 (m, 1H), 2.06 - 1.83 (m, 4H), 1.82 - 1.71 (m, 1H), 1.67 - 1.49 (m, 3H), 1.29 - 1.18 (m, 2H).

[0431] Example 16 (Compound 154)

[0432] First Step: Synthesis of compound 154b

[0433] Hydrazine hydrate (3.47 g, 69.36 mmol) was added to a solution of compound 154a (synthesis method reference patent WO2022106857A1 page 148 example 157 first step) (5.00 g, 34.68 mmol) in ethanol (50 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 3 / 1) to obtain compound 154b (1.00 g). MS m / z (ESI): 145.15 [M+1] + .

[0434] Second Step: Synthesis of compound 154

[0435] Trimethyl orthoformate (194.4 mg, 1.83 mmol) was added to a solution of compound 154b (198.3 mg, 1.37 mmol) in 1,4-dioxane (2 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 hour, then cooled to room temperature, and a solution of compound 23g (100.0 mg, 0.45 mmol) and acetic acid (27.5 mg, 0.45 mmol) in 1,4-dioxane (2 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 154 (24.6 mg). MS m / z (ESI): 353.80 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.47 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.11 (s, 1H), 3.71 - 3.63 (m, 1H), 3.29 - 3.21 (m, 1H), 2.49 - 2.45 (m, 1H), 2.40 - 2.28 (m, 4H), 1.62 - 1.50 (m, 2H), 1.30 (s, 3H).

[0436] Example 17 (Compound 167)

[0437] First Step: Synthesis of Compound 167b

[0438] Trimethyl orthoformate (97.2 mg, 0.91 mmol) was added to a solution of compound 167a (166.6 mg, 0.68 mmol) (synthesis method refer to WO2020112706 A1 page 147 example 127 step A) in 1,4-dioxane (2 mL) at room temperature, after the reaction mixture was stirred at 45 °C for 1 h, it was cooled to room temperature, a solution of compound 23g (50 mg, 0.23 mmol) and acetic acid (13.7 mg, 0.23 mmol) in 1,4-dioxane (2 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 3 / 1) to give compound 167b (20 mg). MS m / z (ESI): 451.20 [M+1] + .

[0439] Second Step: Synthesis of Compound 167

[0440] Hydrochloric acid / 1,4-dioxane (4.0 M, 0.5 mL) was added to a solution of compound 167b (20 mg, 0.04 mmol) in 1,4-dioxane (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 167 (0.61 mg). MS m / z (ESI): 351.00 [M+1] + .

[0441] Example 18 (Compound 35)

[0442] Step 1: Synthesis of compound 35b

[0443] Trimethylorthoformate (18.2 mg, 0.17 mmol) was added to a solution of compound 35a (62.1 mg, 0.23 mmol) (synthetic method reference: Journal of Medicinal Chemistry (2021), 64(15), 10641-10665 synthesis of compound 9e) in 1,4-dioxane (1 mL), after the reaction mixture was stirred at 45 °C for 1 h, acetic acid (8.62 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the mixture, and the reaction mixture was stirred at 120 °C for 15 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 1) to give compound 35b (40 mg). MS m / z (ESI): 609.2 [M+1] + .

[0444] Step 2: Synthesis of compound 35

[0445] Trifluoroacetic acid (0.5 ml) was added to a solution of compound 35b (40 mg, 0.06 mmol) in dichloromethane (1.5 ml), and the reaction mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was adjusted to pH = 8 with ammonia water, concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 35 (10.1 mg). MS m / z (ESI): 379.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.25 (s, 0.42H), 7.36 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.02 (s, 2H), 3.90-3.84 (m, 1H), 2.61-2.53 (m, 1H), 2.19-2.06 (m, 2H), 2.04-1.84 (m, 7H), 1.72-1.65 (m, 1H), 1.64-1.55 (m, 1H).

[0446] Example 19 (compound 73)

[0447] Step 1: Synthesis of compound 73a

[0448] Acetyl chloride (64.2 mg, 0.81 mmol) was added dropwise to a solution of compound 1c (190 mg, 0.54 mmol) and triethylamine (82.8 mg, 0.81 mmol) in dichloromethane (2.0 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 10 / 1) to give compound 73a (55 mg). MS m / z (ESI): 260.0 [M+1] + .

[0449] Second Step: Synthesis of compound 73b

[0450] Lawesson's reagent (104.9 mg, 0.26 mmol, CAS: 19172-47-5) was added to a solution of compound 73a (45 mg, 0.17 mmol) in tetrahydrofuran (1.0 mL) at room temperature. The reaction mixture was stirred at 70 °C for 16 h. After completion of the reaction, the reaction was concentrated under reduced pressure to give compound 73b (50 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 275.9 [M+1] + .

[0451] Third Step: Synthesis of compound 73c

[0452] Trimethylsulfoxonium tetrafluoroborate (80.3 mg, 0.54 mmol) was added to a solution of compound 73b (50 mg, 0.18 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction was quenched by the addition of saturated sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 73c (60 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 289.9 [M+1] + .

[0453] Fourth Step: Synthesis of compound 73d

[0454] Compound 168a (52.3 mg, 0.22 mmol) was added to a solution of compound 73c (60 mg, 0.20 mmol) and triethylamine (25.1 mg, 0.24 mmol) in n-butanol (1.0 mL) at room temperature. The reaction mixture was stirred at 130 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give compound 73d (80 mg, crude), which was used in the next step without purification. MS m / z (ESI): 453.4 [M+1] + .

[0455] Fifth Step: Synthesis of compound 73

[0456] Compound 73d (75 mg, 0.16 mmol) was dissolved in formic acid (1 mL) and stirred at room temperature for 4 h. After the reaction was completed, the reaction mixture was purified by reverse phase preparative (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% FA); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to give compound 73 (8.4 mg). MS m / z (ESI): 353.0 [M+1] + .

[0457] Example 20 (compound 74)

[0458] First Step: Synthesis of compound 74a

[0459] Compound 1d (65.6 mg, 0.30 mmol) was added to a solution of compound 73c (80 mg, 0.27 mmol) and triethylamine (33.5 mg, 0.33 mmol) in n-butanol (0.5 mL) at room temperature. The reaction mixture was stirred at 130 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse phase preparative (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to give compound 74a (14.0 mg). MS m / z (ESI): 439.1 [M+1] + .

[0460] Second Step: Synthesis of compound 74

[0461] Compound 74a (12 mg, 0.027 mmol) was dissolved in formic acid (0.5 mL), the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was freeze-dried to obtain compound 74 (7.2 mg). MS m / z (ESI): 339.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.50 - 4.38 (m, 1H), 4.34 - 4.25 (m, 1H), 4.24 - 4.09 (m, 3H), 4.02 - 3.92 (m, 1H), 3.78 - 3.71 (m, 1H), 2.44 (s, 3H), 1.62 - 1.47 (m, 2H).

[0462] Example 21 (Compound 75)

[0463] First Step: Synthesis of compound 75a

[0464] Compound 8a (74.1 mg, 0.30 mmol) was added to a solution of compound 73c (80 mg, 0.27 mmol) and triethylamine (33.5 mg, 0.33 mmol) in n-butanol (0.5 mL) at room temperature, and the reaction mixture was stirred at 130 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by reverse phase preparation (column: Airs Science Flash C18-M Column, 20 g, 20-35 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-40%; flow rate: 25 mL / min; wavelength: 214 nm) to obtain compound 75a (16.0 mg). MS m / z (ESI): 469.1 [M+1] + .

[0465] Second Step: Synthesis of compound 75

[0466] Formic acid (0.5 mL) was added to compound 75a (13 mg, 0.028 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was freeze-dried to obtain compound 75 (6.3 mg). MS m / z (ESI): 367.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1.4H), 7.37 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 4.06 - 3.98 (m, 1H), 3.40 - 3.30 (m, 3H), 2.99 - 2.87 (m, 2H), 2.65 - 2.60 (m, 1H), 2.43 (s, 3H), 2.14 - 2.03 (m, 2H), 1.97 - 1.88 (m, 2H), 1.71 - 1.59 (m, 2H).

[0467] Example 22 (Compound 77)

[0468] First Step: Synthesis of compound 77a

[0469] Trimethyl orthoformate (183.6 mg, 1.73 mmol) was added to a solution of compound 168a (265.6 mg, 1.15 mmol) in 1,4-dioxane (10 mL) at room temperature. After the reaction mixture was stirred at 45 °C for 1 h, a solution of compound 135d (100 mg, 0.38 mmol) and acetic acid (46.2 mg, 0.77 mmol) in 1,4-dioxane (5 mL) was added to the mixture. The reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the mixture was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 9 / 1) to give compound 77a (60 mg, yield 32.3%). MS m / z (ESI): 481.35 [M+1] + .

[0470] Second Step: Synthesis of compound 77

[0471] Bromotrimethylsilane (311.6 mg, 1.24 mmol) was added to a solution of compound 77a (60 mg, 0.12 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile / water (0.1% formic acid; gradient: 25-90%; column temperature: 25 °C; flow rate: 15 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 77 (8.1 mg). MS m / z (ESI): 366.9 [M+1] +1H NMR (400 MHz, CD3OD) δ 8.50 (d, J = 6.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.61 - 6.52 (m, 1H), 5.00 - 4.90 (m, 1H), 4.38 - 4.20 (m, 1H), 3.68 - 3.35 (m, 3H), 3.27 - 3.09 (m, 2H), 2.91 - 2.75 (m, 1H), 2.72 - 2.33 (m, 3H), 2.29 - 2.17 (m, 1H), 2.13 - 1.97 (m, 1H), 1.96 - 1.75 (m, 2H).

[0472] Example 23 (Compound 82)

[0473] First Step: Synthesis of compound 82b

[0474] Compound 82a (950 mg, 3.90 mmol) was dissolved in methanol (10 mL), hydrazine hydrate (780.94 mg, 15.6 mmol) was added. The reaction mixture was stirred at 50 °C overnight. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM:MeOH = 0-10%) to obtain compound 82b (750 mg).

[0475] Second Step: Synthesis of compound 82c

[0476] Compound 82b (73.14 mg, 0.32 mol) was dissolved in 1,4-dioxane (1 mL), and trimethyl orthoformate (46.16 mg, 0.43 mmol) was added. After the reaction mixture was stirred at 45 °C for 1 hour, it was cooled to room temperature, compound 1c (100 mg, 0.29 mmol) and acetic acid (17.41 mg, 0.29 mmol) were added, and the mixture was stirred at 120 °C overnight. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (15 mL), extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to obtain compound 82c (100 mg, crude). The product was used directly in the next step without purification. MS m / z (ESI): 569.1 [M+1] + .

[0477] Third Step: Synthesis of compound 82

[0478] Compound 82c (100 mg, crude) was dissolved in hydrochloric acid 1,4-dioxane (2 mL) solution, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Durashell C18(A) 21.2x250mm, 10nm; mobile phase: (10mM NH4HCO3); gradient: 25-50%; column temperature: 25°C; flow rate: 15 mL / min; wavelength: 214nm; column pressure: 80bar) to give compound 82 (7.09 mg). MS m / z (ESI): 339.0 [M+1] + .1H NMR (400 MHz, DMSO-d6) δ 8.66 - 8.35 (m, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.13 (d, J = 7.6 Hz, 1H), 4.05 (d, J = 7.6 Hz, 1H), 3.78 - 3.65 (m, 1H), 2.70 - 2.64 (m, 1H), 1.66 (s, 3H), 1.63 - 1.50 (m, 2H).

[0479] Example 24 (Compound 95)

[0480] First Step: Synthesis of compound 95b

[0481] Trimethyl orthoformate (30 mg, 0.29 mmol) was added to a solution of compound 95a (synthesis method reference patent WO2017021920A1 specification page 240 paragraph 1061-1062 synthesis of compound 112) (41 mg, 0.29 mmol) in 1,4-dioxane (1 mL) at room temperature, after the reaction mixture was stirred at 45°C for 1 hour, acetic acid (9 mg, 0.14 mmol) and compound 1c (50 mg, 0.14 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 120°C for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 95b (50 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 484.30 [M+1] + .

[0482] Second Step: Synthesis of compound 95

[0483] Trifluoroacetic acid (0.5 mL) was added to compound 95b (50 mg, 0.10 mmol) in 1,4-dioxane (1 mL), the reaction mixture was stirred at 25 °C for 2 h. After the reaction was completed, the reaction solution was adjusted to pH = 8 with ammonia water, and the mixture was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 95 (8.5 mg). MS m / z (ESI): 354.10 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.99-3.88 (m, 2H), 3.85-3.76 (m, 1H), 3.54-3.51 (m, 1H), 3.45-3.36 (m, 2H), 3.34-3.21 (m, 1H), 1.93-1.66 (m, 5H), 1.59-1.51 (m, 1H).

[0484] Example 25 (compound 96)

[0485] First step: synthesis of compound 96b

[0486] Trimethyl orthoformate (30.4 mg, 0.28 mmol) was added to a solution of compound 96a (synthesis method reference Journal of Medicinal Chemistry (2008), 51(15), 4430-4448 synthesis of compound 8a) (45.1 mg, 0.28 mmol) in 1,4-dioxane (1 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. Then cooled to room temperature, a solution of compound 1c (50.0 mg, 0.14 mmol) and acetic acid (8.6 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 3 / 1) to give compound 96b (50 mg). MS m / z (ESI): 497.35 [M+1] + .

[0487] Second step: synthesis of compound 96

[0488] Hydrochloric acid-1,4-dioxane (4.0 M, 0.5 mL) was added to a solution of compound 96b (50.0 mg, 0.10 mmol) in 1,4-dioxane (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 96 (10.2 mg). MS m / z (ESI): 366.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.14 (s, 0.25H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.82 - 3.76 (m, 1H), 3.29 - 3.10 (m, 4H), 2.91 - 2.74 (m, 2H), 2.66 (s, 3H), 2.22 - 2.06 (m, 2H), 2.01 - 1.83 (m, 2H), 1.74 - 1.68 (m, 1H), 1.54 - 1.49 (m, 1H).

[0489] Example 26 (compound 99)

[0490] First step: synthesis of compound 99b

[0491] Hydrazine hydrate (164.2 mg, 1.28 mmol) was added to a solution of compound 99a (100 mg, 0.64 mmol) in ethanol (2 mL) at room temperature. The reaction mixture was stirred at 80 °C for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 1 / 0 ~ 5 / 1) to give compound 99b (70 mg). MS m / z (ESI): 157.1 [M+1] + .

[0492] Second step: synthesis of compound 99c

[0493] Trifluoroacetic acid (0.3 mL) was added to a solution of compound 99c (15 mg, 0.030 mmol) in tetrahydrofuran (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 99 (5.2 mg). MS m / z (ESI): 366.0 [M+1] + .

[0494] Step 3: Synthesis of compound 99

[0495] Trifluoroacetic acid (0.3 mL) was added to a solution of compound 99c (15 mg, 0.030 mmol) in tetrahydrofuran (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 99 (5.2 mg). MS m / z (ESI): 366.0 [M+1] + .

[0496] Example 27 (compound 97)

[0497] Step 1: Synthesis of compound 97b

[0498] N,N'-carbonyldiimidazole (311.4 mg, 1.92 mmol) was added to a solution of compound 97a (250 mg, 1.60 mmol) and hydrazine hydrate (128.2 mg, 2.56 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (DCM / MeOH = 1 / 0 ~ 3 / 1) to give compound 97b (200 mg). MS m / z (ESI): 171.15 [M+1] + .

[0499] Step 2: Synthesis of compound 97c

[0500] Compound 97b (48.8 mg, 0.28 mmol) in 1,4-dioxane (1 mL) at room temperature, the reaction mixture was stirred at 45 °C for 1 h, then cooled to room temperature, a solution of compound 1c (50.0 mg, 0.14 mmol) and acetic acid (8.6 mg, 0.14 mmol) in 1,4-dioxane (1 mL) was added, the reaction mixture was stirred at 120 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (DCM / MeOH = 1 / 0 ~ 3 / 1) to give compound 97c (50 mg). MS m / z (ESI): 510.30 [M+1] + .

[0501] Third Step: Synthesis of compound 97

[0502] Compound 97c (50.0 mg, 0.098 mmol) in 1,4-dioxane (1 mL) at room temperature, the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 97 (1.0 mg). MS m / z (ESI): 379.85 [M+1] + .

[0503] Example 28 (Compound 180-1)

[0504] First Step: Synthesis of compound 180b

[0505] Compound 180a (2.0 g, 12.48 mmol) in ethanol (40 mL) at room temperature, the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 1 / 10) to give 180b (1.6 g). MS m / z (ESI): 161.10 [M+1] + .

[0506] Second Step: Synthesis of compound 180c

[0507] Compound 180b (1.5 g, 9.36 mmol) was added to a solution of trimethyl orthoformate (993.8 mg, 9.36 mmol) in 1,4-dioxane (30 mL) at room temperature, and the reaction mixture was stirred at 45 °C for 1 h. Then acetic acid (562.4 mg, 9.36 mmol) and intermediate 23g (2.04 g, 9.36 mmol) were added to the reaction mixture, which was stirred at 120 °C for 17 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 1 / 30) to give compound 180c (1.0 g). MS m / z (ESI): 369.70 [M+1] + .

[0508] Third Step: Synthesis of compound 180

[0509] Compound 180c (100 mg, 0.27 mmol) was added to a solution of hydrochloric acid-1,4 dioxane (4.0 M, 4.0 mL), and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography-preparation (column: Gemini5um C 18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 180-1. MS m / z (ESI): 329.90 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.56 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 5.82 - 5.47 (m, 1H), 4.91 - 4.80 (m, 2H), 3.98 - 3.72 (m, 3H), 2.63 - 2.56 (m, 1H), 1.76 - 1.63 (m, 1H), 1.61 - 1.48 (m, 1H).

[0510] Example 29 (Compound 179)

[0511] First Step: Synthesis of compound 179b

[0512] Hydrazine hydrate (4.81 g, 76.85 mmol) was added to a solution of compound 179a (2 g, 19.21 mmol) in methanol (20 mL) at room temperature, and the reaction mixture was stirred at 50 °C for 15 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (MeOH / DCM = 0-50%) to give compound 179b (1.30 g). MS m / z (ESI): 105.10 [M+1] + .

[0513] Second Step: Synthesis of compound 179

[0514] N,N-dimethylformamide dimethyl acetal (228.9 mg, 1.92 mmol) was added to a solution of compound 179b (200 mg, 1.92 mmol) in 1,4-dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 1 h and then cooled to room temperature. A solution of compound 23g (418.9 mg, 1.92 mmol) and acetic acid (115.36 mg, 1.92 mmol) in 1,4-dioxane (5 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 15 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 179 (23.4 mg). MS m / z (ESI): 313.65 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.50 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.80 (s, 1H), 3.84 - 3.71 (m, 3H), 2.97 (t, J = 7.0 Hz, 2H), 2.48 - 2.44 (m, 1H), 1.72 - 1.62 (m, 1H), 1.58 - 1.49 (m, 1H).

[0515] Example 30 (compound 175-1-P2)

[0516] Compound 12-1-P2 (50 mg, 0.15 mmol) was dissolved in acetone (2 mL) at 0 °C, and sodium triacetylboration hydride (81.2 mg, 0.38 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL x 2), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 175-1-P2 (47.3 mg). MS m / z (ESI): 381.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.11 - 3.84 (m, 2H), 3.83 - 3.75 (m, 2H), 3.57 - 3.42 (m, 2H), 3.37 - 3.19 (m, 1H), 2.63 - 2.55 (m, 2H), 2.34 - 2.20 (m, 1H), 1.75 - 1.69 (m, 1H), 1.58 - 1.52 (m, 1H), 1.29 (d, J = 6.4 Hz, 6H).

[0517] Example 31 (Compound 186)

[0518] First Step: Synthesis of compound 186a

[0519] Diisobutylaluminum hydride (15.3 mL, 15.36 mmol) was added to a solution of compound 23d (3.70 g, 12.79 mmol) in dichloromethane (40 mL) under nitrogen at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 2 / 1) to obtain compound 186a (620 mg). MS m / z (ESI): 244.95 [M+1] + .

[0520] Second Step: Synthesis of compound 186c

[0521] Potassium carbonate (1.39 g, 10.12 mmol), compound 186b (850.4 mg, 4.43 mmol) were added to a solution of compound 186a (620 mg, 2.53 mmol) in methanol (15 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was filtered and washed with ethyl acetate (20 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 0 ~ 5 / 1) to give compound 186c (440 mg). MS m / z (ESI): 240.95 [M+1] + .

[0522] Step 3: Synthesis of compound 186e

[0523] Sodium azide (415.8 mg, 6.39 mmol) was added to a solution of compound 186c (800 mg, 3.198 mmol) in N,N-dimethylformamide (8 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 186e (600 mg). MS m / z (ESI): 157.05 [M-55] + .

[0524] Step 4: Synthesis of compound 186f

[0525] Compound 186e (105.64 mg, 0.498 mmol), chloro(5-methyl-2-(4-(4-(4- methoxyphenyl)piperidin-1-yl)phenyl)cyclopenta-1,2-dienyl) ruthenium (II) (18.1 mg, 0.025 mmol) were added to a solution of compound 186c (60 mg, 0.25 mmol) in 1,4-dioxane (5 mL) under nitrogen protection. The reaction mixture was stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 30 / 1) to give compound 186f (50 mg). MS m / z (ESI): 453.35 [M+1] + .

[0526] Step 5: Synthesis of compound 186

[0527] Bromotrimethylsilane (82.9 mg, 0.33 mmol) was added to a solution of compound 186f (50 mg, 0.11 mmol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 186 (11.2 mg). MS m / z (ESI): 339.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.54 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 5.41 (s, 1H), 3.89 - 3.32 (m, 2H), 3.31 - 3.06 (m, 2H), 2.46 - 2.17 (m, 3H), 2.16 - 2.05 (m, 1H), 1.63 - 1.43 (m, 2H).

[0528] Example 32 (Compound 177)

[0529] First Step: Synthesis of compound 177a

[0530] Tert-butyldimethylsilyl chloride (8.09 g, 53.65 mmol) was added to a solution of imidazole (5.62 g, 82.54 mmol) and compound 23g (9 g, 41.27 mmol) in dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-20%) to give compound 177a (9 g). MS m / z (ESI): 332.15 [M+1] + .

[0531] Second Step: Synthesis of compound 177c

[0532] Compound 177b (0.36 mL, 2.32 mmol) was added to a solution of compound 177a (700 mg, 2.11 mmol) and diisopropylethylamine (299.4 mg, 2.32 mmol) in dichloromethane (200 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours, and the reaction solution was used directly in the next step.

[0533] Third Step: Synthesis of compound 177e

[0534] Compound 177d (325.8 mg, 3.74 mmol) was added to the reaction solution of compound 177c in dichloromethane at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 50%) to obtain compound 177e (800 mg). MS m / z (ESI): 461.30 [M+1] + .

[0535] Fourth step: synthesis of compound 177f

[0536] Methyl iodide (0.28 mL, 3.47 mmol) was added to a solution of compound 177e (800 mg, 1.73 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 177f (800 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 474.95 [M+1] + .

[0537] Fifth step: synthesis of compound 177g

[0538] Hydrazine hydrate (0.077 mL, 1.26 mmol) was added to a solution of compound 177f (200 mg, 0.42 mmol) in ethanol (2 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 177g (200 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 345.05 [M+1] + .

[0539] Sixth step: synthesis of compound 177

[0540] Compound 177g (200 mg, 0.43 mmol) was added to a solution of p-toluenesulfonic acid (82.8 mg, 0.43 mmol) and trimethyl orthoformate (0.19 mL, 1.74 mmol) in ethanol (3 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 177 (25.8 mg). MS m / z (ESI): 355.20 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.18 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.54 (s, 1H), 3.92 - 3.76 (m, 4H), 3.57 - 3.51 (m, 1H), 2.56 - 2.53 (m, 1H), 1.63 - 1.49 (m, 2H), 1.41 (s, 3H).

[0541] Example 33 (Compound 176)

[0542] First Step: Synthesis of compound 176a

[0543] Compound 177b (1.05 g, 4.52 mmol) was added to a solution of compound 113a (1.00 g, 4.30 mmol) and diisopropylethylamine (612.5 mg, 4.74 mmol) in dichloromethane (20 mL) at 0 °C, the reaction mixture was stirred at room temperature for 2 hours, the reaction solution was used directly in the next step without treatment.

[0544] Second Step: Synthesis of compound 176b

[0545] Morpholine (635.6 mg, 7.29 mmol) was added to a solution of 176a (4.52 mmol) in dichloromethane (20 mL) at 0 °C, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0%-50%) to obtain compound 176b (1.10 g). MS m / z (ESI): 361.15 [M+1] + .

[0546] Third Step: Synthesis of compound 176d

[0547] Potassium tert-butoxide (310.6 mg, 2.76 mmol) was added to a solution of compound 176b (1.00 g, 2.76 mmol) in tetrahydrofuran (20 mL) at room temperature, after the reaction mixture was stirred at room temperature for 10 minutes, compound 176c (515.5 mg, 2.76 mmol) was added, and the reaction mixture was continued to stir at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water, extracted with ethyl acetate (50 mL x 3), and the combined organic phase was concentrated under reduced pressure to obtain compound 176d (1 g, crude), which was used directly in the next step without purification. MS m / z (ESI): 375.20 [M+1] + .

[0548] Fourth Step: Synthesis of compound 176e

[0549] Trifluoroacetic acid (151.9 mg, 1.33 mmol) was added to a solution of compound 176d (1.00 g, 2.66 mmol) and compound formylhydrazide (320 mg, 5.33 mmol) in 1,4-dioxane (20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0% - 5%) to give compound 176e (400 mg). MS m / z (ESI): 369.20 [M+1] + .

[0550] Fifth step: synthesis of compound 176

[0551] Boron tribromide (508.8 mg, 2.03 mmol) was added to a solution of compound 176e (150 mg, 0.40 mmol) in dichloromethane (5 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was quenched with methanol (1 mL) and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 176 (6.2 mg). MS m / z (ESI): 354.80 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.34 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 3.75 - 3.60 (m, 5H), 3.24 - 3.11 (m, 4H), 2.58 - 2.53 (m, 1H), 1.67 - 1.58 (m, 2H).

[0552] Example 34 (compound 197)

[0553] First step: synthesis of compound 197b

[0554] Hydrazine hydrate (347.2 mg, 6.93 mmol) was added to a solution of compound 197a (500 mg, 3.46 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 1) to obtain compound 197b (300 mg). MS m / z (ESI): 145.20 [M+1] + .

[0555] Second Step: Synthesis of compound 197

[0556] N,N-dimethylformamide dimethyl acetal (109.3 mg, 0.91 mmol) was added to a solution of compound 197b (132.2 mg, 0.91 mmol) in 1,4-dioxane (1 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 1 h. After that, acetic acid (55.1 mg, 0.91 mmol) and compound 197c (200 mg, 0.91 mmol) were added, and the reaction mixture was heated to 120 °C and stirred for 15 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 197 (14.5 mg). MS m / z (ESI): 354.10 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.48 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.72 (s, 1H), 4.16 (s, 1H), 3.78 - 3.70 (m, 1H), 3.38 - 3.33 (m, 1H), 2.57 - 2.52 (m, 1H), 2.33 - 2.26 (m, 1H), 2.04 - 1.92 (m, 2H), 1.85 - 1.72 (m, 2H), 1.67 - 1.51 (m, 3H).

[0557] Example 35 (compound 198)

[0558] First Step: Synthesis of compound 198b

[0559] Compound 198a (1200 mg, 14.1 mmol) was added to 176a (6.46 mmol) (synthesis method, refer to Example 33

[0560] A solution of compound 176a (1 g, 2.78 mmol) in dichloromethane (30 mL) was added sodium borohydride (105.3 mg, 2.78 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0%-50%) to give compound 198b (2 g). MS m / z (ESI): 358.85 [M+1] + .

[0561] Second Step: Synthesis of compound 198c

[0562] Sodium borohydride (105.3 mg, 2.78 mmol) was added to a solution of compound 198b (500 mg, 1.39 mmol) in methanol (10 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0%-75%) to give compound 198c (440 mg). MS m / z (ESI): 360.85 [M+1] + .

[0563] Third Step: Synthesis of compound 198d

[0564] Iodomethane (172.8 mg, 1.21 mmol) was added to a solution of compound 198c (400 mg, 1.11 mmol) in ethanol (6 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 198d (340 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 374.85 [M+1] + .

[0565] Fourth Step: Synthesis of compound 198e

[0566] 4-Dimethylaminopyridine (208.3 mg, 1.70 mmol), N,N-diisopropylethylamine (220.4 mg, 1.70 mmol), and tert-butyldimethylsilyl chloride (192.8 mg, 1.28 mmol) were added to a solution of compound 198d (340 mg, 0.85 mmol) in dichloromethane (10 mL) at room temperature, and the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0%-5%) to give compound 198e (300 mg). MS m / z (ESI): 488.90 [M+1] + .

[0567] Fifth Step: Synthesis of compound 198f

[0568] Formylhydrazide (176e) (71.2 mg, 1.19 mmol) and trifluoroacetic acid (33.8 mg, 0.30 mmol) were added to a solution of compound 198e (290 mg, 0.59 mmol) in 1,4-dioxane (5 mL) at room temperature. The reaction mixture was stirred at 80 °C for 10 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 0% - 5%) to give compound 198f (100 mg, yield 33.8%). MS m / z (ESI): 483.35 [M+1] + .

[0569] Sixth step: synthesis of compound 198

[0570] Lithium chloride (175.3 mg, 4.14 mmol) and p-toluenesulfonic acid (393.4 mg, 2.07 mmol) were added to a solution of compound 198f (50 mg, 0.10 mmol) in N,N-dimethylformamide (3 mL) at room temperature. The reaction mixture was stirred at 150 °C for 36 h. After the reaction was completed, the reaction solution was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% ammonia water); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 198 (1.3 mg). MS m / z (ESI): 354.95 [M+1] + .

[0571] Example 36 (compound 196-1-P1, 196-1-P2)

[0572] First step: synthesis of compound 196b-1

[0573] Compound 196a-1 (1.48 g, 6.46 mmol) was added to a solution of DMF-DMA (770 mg, 6.46 mmol) in 1,4-dioxane (15 mL) at room temperature. After the reaction mixture was stirred at 80 °C for 30 min, acetic acid (0.37 mL, 6.46 mmol) and compound 113a (1.5 g, 6.46 mmol) were added to the reaction solution. The reaction mixture was stirred at 110 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 1 / 30) to give compound 196b-1 (1.2 g). MS m / z (ESI): 453.15 [M+1] + .

[0574] Step 2: Synthesis of compound 196c-1

[0575] Compound 196b-1 (800 mg, 1.76 mmol) was added to a solution of deuterated methanol (8 mL) at room temperature. After the reaction mixture was stirred at 60 °C for 16 h, the reaction mixture was concentrated under reduced pressure to give compound 196c-1 (800 mg, crude). MS m / z (ESI): 454.15 [M+1] + .

[0576] Step 3: Synthesis of compound 196-1-P1, 196-1-P2

[0577] Boron tribromide (1.32 g, 5.28 mmol) was added to a solution of compound 196c-1 (800 mg, 1.761 mmol) in dichloromethane (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C 18 18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 196d-1 (300 mg). Compound 196d-1 was further resolved by supercritical fluid chiral chromatography (preparative column: SHIMADZU SFC-40P, 30mm I.D.*250mm L, 10um; flow rate: 100 mL / min column temperature: room temperature; mobile phase: A: CO2 B: ethanol of 0.1% DEA) to give compound 196-1-P1 (57.3 mg) and 196-1-P2 (84.5 mg).

[0578] Compound 196-1-P1: MS m / z (ESI): 339.80 [M+1] + , supercritical fluid chromatography SFC: retention time = 6.944 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) d 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.85 - 3.46 (m, 3H), 3.25 - 3.11 (m, 1H), 2.99 - 2.79 (m, 2H), 2.58 - 2.52 (m, 1H), 2.17 - 1.90 (m, 2H), 1.76 - 1.62 (m, 1H), 1.59 - 1.48 (m, 1H).

[0579] Compound 196-1-P2: MS m / z (ESI): 340.10 [M+1] +Supercritical fluid chromatography SFC: Retention time = 8.761 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.84 - 3.71 (m, 2H), 3.52 - 3.48 (m, 1H), 3.22 - 3.17 (m, 1H), 3.03 - 2.78 (m, 2H), 2.58 - 2.53 (m, 1H), 2.31 - 1.95 (m, 2H), 1.77 - 1.65 (m, 1H), 1.60 - 1.48 (m, 1H).

[0580] Example 37 (Compound 199)

[0581] First Step: Synthesis of compound 199b

[0582] Methylmagnesium bromide (1.0 M in THF) (16.5 mL, 16.5 mmol) was added to a solution of compound 199a (1.00 g, 5.87 mmol) and cerium chloride (6.12 g, 16.45 mmol) in tetrahydrofuran (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. After completion of the reaction, the reaction was quenched with ice water (20 mL), extracted with ethyl acetate (100 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 199b (1.00 g, crude), which was used directly in the next step without purification.

[0583] Second Step: Synthesis of compound 199c

[0584] Hydrazine hydrate (537.5 mg, 10.73 mmol) was added to a solution of compound 199b (1.00 g, 5.37 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After completion of the reaction, the reaction was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 1) to give compound 199c (120 mg). MS m / z (ESI): 171.15 [M-1] + .

[0585] Third Step: Synthesis of compound 199

[0586] To a solution of compound 199c (126.6 mg, 0.58 mmol) in 1,4-dioxane (1 mL) was added N,N-dimethylformamide dimethyl acetal (69.2 mg, 0.58 mmol) at room temperature. After the reaction mixture was stirred at 80 °C for 1 h, acetic acid (34.8 mg, 0.58 mmol) and compound 23g (100 mg, 0.58 mmol) were added to the mixture. The reaction mixture was heated to 120 °C and stirred for 15 h. After the reaction was completed, the reaction mixture was concentrated. The residue was purified by preparative high performance liquid chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 199 (3.8 mg). MS m / z (ESI): 381.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.45 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.06 (s, 1H), 3.81 - 3.75 (m, 1H), 2.91 - 2.80 (m, 1H), 2.56 - 2.53 (m, 1H), 2.00 - 1.86 (m, 2H), 1.71 - 1.55 (m, 6H), 1.38 - 1.29 (m, 2H), 1.11 (s, 3H).

[0587] Example 38 (compound 201)

[0588] First Step: Synthesis of compound 201b

[0589] To a solution of compound 201a (615.2 mg, 5.34 mmol) in dichloromethane (20 mL) was added compound 177c (3.16 mmol) (synthesis method was referred to the synthesis of compound 177c in Example 32, second step) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 0% - 50%) to give compound 201b (1.40 g). MS m / z (ESI): 489.20 [M+1] + .

[0590] Second Step: Synthesis of compound 201c

[0591] Methyliodide (753.8 mg, 5.31 mmol) was added to a solution of compound 201b (1.30 g, 2.65 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 85 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 201c (1.30 g, crude), which was used directly in the next step without purification. MS m / z (ESI): 503.40 [M+1] + .

[0592] Step 3: Synthesis of compounds 201d and 201e

[0593] Hydrazine hydrate (238.6 mg, 4.76 mmol) was added to a solution of compound 201c (1.20 g, 2.38 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give mixture 201d and 201e (1.00 g, crude), which was used directly in the next step without purification.

[0594] Step 4: Synthesis of compound 201

[0595] Compound 201d (1.00 g, 2.68 mmol) was added to a solution of p-toluenesulfonic acid (509.5 mg, 2.68 mmol) and trimethyl orthoformate (1.13 g, 10.71 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 201 (30.0 mg). MS m / z (ESI): 383.20 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.28 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.28 (s, 1H), 3.80 - 3.73 (m, 1H), 3.30 - 3.23 (m, 1H), 3.22 - 3.10 (m, 3H), 2.55 - 2.51 (m, 1H), 1.70 - 1.55 (m, 3H), 1.52 - 1.40 (m, 3H), 1.12 (s, 3H).

[0596] Example 39 (Compound 207) Example 39 (Compound 207)

[0597] Step 1: Synthesis of compound 207b

[0598] Compound 207a (0.50 g, 3.08 mmol) and diisopropylethylamine (1.14 g, 8.81 mmol) were added to a solution of compound 177c (2.93 mmol) (synthesis method refer to the synthesis of compound 177c in Step 2 of Reference Example 32) in dichloromethane (10 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0% - 70%) to obtain compound 207b (1 g). MS m / z (ESI): 500.90 [M+1] + .

[0599] Step 2: Synthesis of compound 207c

[0600] Methyl iodide (56.6 mg, 0.39 mmol) was added to a solution of compound 207b (100 mg, 0.19 mmol) in ethanol (1.0 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 207c (100 mg, crude), and the product was used directly in the next step without purification. MS m / z (ESI): 515.15 [M+1] + .

[0601] Step 3: Synthesis of compound 207d

[0602] Hydrazine hydrate (38.8 mg, 0.77 mmol) was added to a solution of compound 207c (100 mg, 0.19 mmol) in ethanol (1.0 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 207d (100 mg, crude), and the product was used directly in the next step without purification. MS m / z (ESI): 384.95 [M+1] + .

[0603] Step 4: Synthesis of compound 207

[0604] Compound 207d (80 mg, 0.16 mmol) was added to a solution of p-toluenesulfonic acid (30.5 mg, 0.16 mmol) and trimethyl orthoformate (67.9 mg, 0.64 mmol) in ethanol (1.0 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2 mm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 25-65%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 207 (20.7 mg). MS m / z (ESI): 395.00 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.15 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.88 (s, 1H), 4.07 - 3.92 (m, 4H), 3.55 - 3.49 (m, 1H), 2.56 - 2.53 (m, 1H), 2.20 - 2.11 (m, 4H), 1.64 - 1.49 (m, 2H), 1.12 (s, 3H).

[0605] Example 40 (Compound 206)

[0606] First Step: Synthesis of compound 206c, 206d

[0607] Compound 206b (3.50 g, 13.99 mmol), potassium carbonate (3.36 g, 24.34 mmol) and potassium iodide (6.06 g, 36.50 mmol) were added to a solution of compound 206a (1.20 g, 12.17 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 60 °C and stirred for 18 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to give compound 206c (300 mg) and compound 206d (900 mg).

[0608] Compound 206c: MS m / z (ES): 266.05 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.74 (d, J = 0.8 Hz, 1H), 8.16 (s, 1H), 7.96 (d, J = 1.2 Hz, 1H), 5.32 (d, J = 4.8 Hz, 1H), 3.74 (s, 1H), 3.53 - 3.36 (m, 3H), 2.05 - 1.95 (m, 2H), 1.39 (d, J = 8.4 Hz, 9H).

[0609] Compound 206d: MS m / z (ES): 266.10 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.15 (s, 1H), 7.97 (s, 1H), 4.96 - 4.90 (m, 1H), 3.82 - 3.73 (m, 1H), 3.52 - 3.37 (m, 3H), 2.43 - 2.37 (m, 1H), 2.31 - 2.22 (m, 1H), 1.40 (s, 9H).

[0610] Second Step: Synthesis of compound 206e

[0611] Compound 206c (300 mg, 1.13 mmol) was dissolved in 1,4-dioxane (15 mL), and p-toluenesulfonylhydrazide (210.6 mg, 1.13 mmol) was added. The reaction mixture was stirred at 80 °C for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 206e (300 mg, crude product), which was used directly in the next step without purification. MS m / z (ESI): 434.05 [M+1] + .

[0612] Third Step: Synthesis of compound 206h

[0613] Sodium hydride (2.34 g, 97.54 mmol) was added to a solution of compound 206g (29.56 g, 73.16 mmol) in tetrahydrofuran (200 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. Compound 206f (10 g, 48.77 mmol) (synthesis method, refer to patent WO2016123164 A1, page P51, Example 36 step A, synthesis of compound Benzaldehyde, 2,3-dichloro-6-methoxy) was added. After the reaction was completed, the reaction solution was quenched with saturated brine (200 mL), extracted with ethyl acetate (200 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 10) to obtain compound 206h (5.20 g).1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.76 (dd, J = 18.0, 12.0 Hz, 1H), 5.96 (dd, J = 17.6, 2.0 Hz, 1H), 5.66 (dd, J = 11.6, 2.0 Hz, 1H), 3.84 (s, 3H).

[0614] Fourth Step: Synthesis of compound 206i

[0615] Compound 206h (468.4 mg, 2.31 mmol) and compound 206e (500 mg, 1.15 mmol) were added to a solution of cobalt tetraphenylporphyrin (38.7 mg, 0.058 mmol) and cesium carbonate (563.6 mg, 1.73 mmol) in 1,4-dioxane (8 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 1 / 10) to obtain compound 206i (230 mg). MS m / z (ESI): 452.25 [M+1] + .

[0616] Fifth Step: Synthesis of compound 206

[0617] Boron tribromide (332.3 mg, 1.33 mmol) was added to a solution of 206i (200 mg, 0.44 mmol) in dichloromethane (3 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C 18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 206 (105.7 mg). MS m / z (ESI): 337.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.22 - 9.81 (m, 1H), 8.10 - 7.85 (m, 1H), 7.38 - 7.17 (m, 1H), 6.94 - 5.90 (m, 2H), 5.31 - 5.13 (m, 1H), 3.81 - 3.64 (m, 1H), 3.58 - 3.41 (m, 3H), 2.63 - 2.52 (m, 1H), 2.46 - 2.04 (m, 3H), 1.77 - 1.23 (m, 2H).

[0618] Example 41 (Compound 204-P1, 204-P2)

[0619] First Step: Synthesis of compound 204b-P1, 204b-P2

[0620] Compound 204a (0.76 g, 7.34 mmol) was added to a solution of N,N- dimethylformamide dimethyl acetal (0.87 g, 7.34 mmol) in 1,4-dioxane (20 mL) at room temperature, after the mixture was stirred at 80 °C for 30 min, acetic acid (0.42 mL, 7.34 mmol) and compound 23g (1.60 g, 7.34 mmol) were added, the reaction mixture was stirred at 110 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 1 / 10) to give compound 204b (300 mg).

[0621] Compound 204b (300 mg) was resolved by supercritical fluid chiral chromatography (preparative column: SHIMADZU SFC-40P, Daicel Chiralpak IB N-10SFC, 30 mm I.D.*250 mm L, 10 μm; flow rate: 100 mL / min column temperature: room temperature; mobile phase: A: CO2 B: ethanol 0.1% NH3) to give compound 204b-P1 (80 mg) and compound 204b-P2 (80 mg).

[0622] Compound 204b-P1: supercritical fluid chromatography SFC: retention time 6.615 min, UV = 214 nm. MS m / z (ESI): 313.80 [M+1] + .

[0623] Compound 204b-P2: supercritical fluid chromatography SFC: retention time 7.496 min, UV = 214 nm. MS m / z (ESI): 313.80 [M+1] + .

[0624] Second Step: Synthesis of compound 204-P1

[0625] Compound 204b-P1 (80 mg, 0.25 mmol) was dissolved in a solution of deuterated methanol (2 mL) at room temperature, and the reaction solution was stirred at 60 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (chromatographic column: Gemini 5um C 18150*21.2 mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 204-P1 (73.8 mg). MS m / z (ESI): 315.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 5.0 Hz, 1H), 3.87 - 3.69 (m, 3H), 2.97 (t, J = 7.0 Hz, 2H), 2.49 - 2.44 (m, 1H), 1.74 - 1.62 (m, 1H), 1.59 - 1.47 (m, 1H).

[0626] Third Step: Synthesis of compound 204-P2

[0627] Compound 204b-P2 (80 mg, 0.25 mmol) was dissolved in deuterated methanol (2 mL) at room temperature. The reaction was stirred at 60 °C for 16 hours. The reaction was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 (100*21.2mm); mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 204-P2 (69.8 mg). MS m / z (ESI): 315.05 [M+1] 18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm) to give compound 204-P1 (73.8 mg). MS m / z (ESI): 315.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.79 (t, J = 5.0 Hz, 1H), 3.87 - 3.69 (m, 3H), 2.97 (t, J = 7.0 Hz, 2H), 2.49 - 2.44 (m, 1H), 1.74 - 1.62 (m, 1H), 1.59 - 1.47 (m, 1H).

[0628] Example 42 (compound 214)

[0629] First Step: Synthesis of compound 214a

[0630] Formylhydrazine (31.05 g, 0.52 mol) and trimethyl orthoformate (73.15 g, 0.69 mol) were added to a solution of compound 113a (20 g, 86.17 mmol) in ethanol (200 mL) at room temperature. The reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 20) to give compound 214a (18 g). MS m / z (ESI): 283.95 [M+1] + .

[0631] Second Step: Synthesis of compound 214b

[0632] N-Bromosuccinimide (12.40 g, 69.68 mmol) and azobisisobutyronitrile (10.40 g, 63.35 mmol) were added to a solution of compound 214a (18 g, 63.35 mmol) in dichloromethane (200 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was diluted with water (100 mL), and the pH was adjusted to 7-8 with a saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by Biotage-Flash (column: C18 reverse phase column, acetonitrile-water (0.1% formic acid); gradient: 5%-50%) to give compound 214b (8 g). MS m / z (ESI): 361.65, 363.65 [M+1, M+3] + .

[0633] Third Step: Synthesis of compound 214c

[0634] Boron tribromide (27.60 g, 110.18 mmol) was added to a solution of compound 214b (8 g, 22.04 mmol) in dichloromethane (100 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was quenched with methanol (20 mL) in an ice bath, and the pH was adjusted to 8-9 with triethylamine. The organic phase was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 20) to give compound 214c (4 g). MS m / z (ESI): 347.85, 349.85 [M+1, M+3] + .

[0635] Fourth Step: Synthesis of compound 214

[0636] Compound 214d (166.8 mg, 0.86 mmol), tetrakis triphenyl phosphine palladium (33.1 mg, 0.029 mmol), potassium carbonate (118.8 mg, 0.86 mmol) were added to a mixture of compound 214c (100 mg, 0.29 mmol) in 1,4-dioxane and water (5 mL / 1 mL) at room temperature. The reaction mixture was stirred at 90 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 214 (11.5 mg). MS m / z (ESI): 336.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 10.38 (s, 1H), 8.31 (s, 1H), 8.01 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.98 - 3.83 (m, 1H), 2.76 - 2.62 (m, 1H), 1.73 - 1.61 (m, 1H), 1.53 - 1.40 (m, 1H).

[0637] Example 43 (Compound 208)

[0638] First Step: Synthesis of compound 208b

[0639] Compound 214c (280 mg, 0.80 mmol, synthesis method refer to the synthesis of compound 214c in the third step of Reference Example 42) was dissolved in a mixture of 1,4-dioxane and water (10 mL / 2 mL) under nitrogen protection, and compound 208a (427.0 mg, 1.60 mmol) (synthesis method refer to the synthesis of compound 1,4-Dioxaspiro[4.5]dec-7-ene, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- in Example 32 on page 70 of patent CN 106336413 A), potassium carbonate (332.6 mg, 2.41 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (58.7 mg, 0.080 mmol) were added in turn, and the reaction mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound 208b (180 mg). MS m / z (ESI): 408.0 [M+1] + .

[0640] Second step: synthesis of compound 208c

[0641] Compound 208b (180 mg, 0.441 mmol) was dissolved in a mixture of 1,4-dioxane and formic acid (1 mL / 1 mL) at room temperature. The reaction mixture was stirred at 50°C for 3 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25°C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 208c (40 mg). MS m / z (ESI): 364.0 [M+1] + .

[0642] Third step: synthesis of compound 208

[0643] Methylmagnesium bromide (0.55 mL, 0.55 mmol) was added dropwise to a solution of compound 208c (40 mg, 0.110 mmol) in tetrahydrofuran (2 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 208 (1.7 mg). MS m / z (ESI): 380.0 [M+1] + .

[0644] Example 44 (compound 104, 209-P1, 209-P2)

[0645] First step: synthesis of compound 104-P1, 104-P2

[0646] Compound 214c (500 mg, 1.43 mmol, synthesis method refer to synthesis of compound 214c in example 42, step 3) was dissolved in a mixture of 1,4-dioxane and water (10 mL / 2 mL) under nitrogen protection, and compound 104a (219.9 mg, 1.72 mmol), potassium carbonate (494.9 mg, 3.58 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (104.8 mg, 0.14 mmol) were added in turn. The reaction mixture was stirred at 80 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 30-90%; flow rate: 20 mL / min) to give compound 104 (120 mg). MS m / z (ESI): 352.0 [M+1] + Compound 104 (120 mg) was resolved by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak AD-10 SFC 30 mm I.D.*250 mm L, 10 μm, mobile phase: CO2 / MeOH [0.1% NH3(7M solution in MeOH)], total flow rate: 2.5 mL / min) to give compound 104-P1 (33 mg) and compound 104-P2 (27 mg).

[0647] Compound 104-P1: MS m / z (ESI): 352.0 [M+1] +Supercritical fluid chromatography SFC: Retention time = 4.661 min

[0648] Compound 104-P2: MS m / z (ESI): 352.0 [M+1] + Supercritical fluid chromatography SFC: Retention time = 5.171 min

[0649] Second Step: Synthesis of compound 209-P1

[0650] Compound 104-P1 (33 mg, 0.093 mmol) was dissolved in deuterated methanol (2 mL) under nitrogen protection, and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 209-P1 (27.6 mg). MS m / z (ES): 352.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.26 - 4.17 (m, 1H), 4.14 - 4.07 (m, 1H), 3.91 - 3.86 (m, 1H), 3.79 (t, J = 5.4 Hz, 2H), 2.72 - 2.64 (m, 1H), 2.59 - 2.52 (m, 2H), 1.71 - 1.64 (m, 1H), 1.57 - 1.51 (m, 1H).

[0651] Third Step: Synthesis of compound 209-P2

[0652] Compound 104-P2 (27 mg, 0.077 mmol) was dissolved in deuterated methanol (2 mL) under nitrogen protection, and the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 209-P2 (26.9 mg). MS m / z (ES): 353.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 4.28 - 4.16 (m, 1H), 4.15 - 4.06 (m, 1H), 3.92 - 3.85 (m, 1H), 3.79 (t, J = 5.6 Hz, 2H), 2.71 - 2.63 (m, 1H), 2.59 - 2.52 (m, 2H), 1.72 - 1.64 (m, 1H), 1.57 - 1.50 (m, 1H).

[0653] Example 45 (Compound 211)

[0654] First Step: Synthesis of Compound 211

[0655] Compound 211a (42.1 mg, 0.26 mmol), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (29.8 mg, 0.052 mmol), cesium carbonate (252.1 mg, 0.77 mmol) and tris(dibenzylideneacetone)dipalladium (23.6 mg, 0.026 mmol) were added to a solution of compound 214c (90 mg, 0.27 mmol, synthesis method refer to Example 42, third step, synthesis of compound 214c) in 1,4-dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 110 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% ammonia water); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 211 (27.6 mg). MS m / z (ESI): 430.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.24-7.13 (m, 1H), 6.71-6.59 (m, 1H), 5.76 (t, J = 56.2 Hz, 1H), 4.06-3.92 (m, 4H), 3.67-3.58 (m, 1H), 2.49-2.43 (m, 3H), 2.23-2.14 (m, 2H), 1.73-1.64 (m, 1H), 1.50-1.40 (m, 1H).

[0656] Example 46 (Compound 212)

[0657] First Step: Synthesis of Compound 212a

[0658] To a solution of compound 177d (89.8 mg, 1.03 mmol), tris(dibenzylideneacetone)dipalladium (78.7 mg, 0.086 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (99.5 mg, 0.17 mmol), cesium carbonate (840.2 mg, 2.58 mmol) in 1,4-dioxane (8 mL) was added compound 214c (300 mg, 0.86 mmol, synthesis was referred to the synthesis of compound 214c in the third step of Example 42) at room temperature. The reaction mixture was stirred at 110 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (HPLC) (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% ammonia); gradient: 60-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 212a (45 mg). MS m / z (ESI): 355.20 [M+1] + .

[0659] Second Step: Synthesis of compound 212

[0660] To a solution of compound 212a (45 mg, 0.13 mmol) in deuterated methanol (1 mL) was added at room temperature. The mixture was stirred at 60 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give compound 212 (24.2 mg). MS m / z (ESI): 356.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.53 (s, 1H), 3.92-3.86 (m, 2H), 3.86-3.82 (m, 1H), 3.81-3.76 (m, 1H), 3.57-3.51 (m, 1H), 2.56-2.52 (m, 1H), 1.63-1.48 (m, 2H), 1.41 (s, 3H).

[0661] Example 47 (compound 213)

[0662] First Step: Synthesis of compound 213b

[0663] To a solution of compound 213a (500 mg, 1.43 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (165.8 mg, 0.29 mmol), cesium carbonate (1.40 g, 4.30 mmol) and tris(dibenzylideneacetone)dipalladium (131.2 mg, 0.14 mmol) in 1,4-dioxane (5 mL) was added compound 214c (156.2 mg, 1.57 mmol) at room temperature. The reaction mixture was stirred at 110 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% TFA); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 213b (150 mg). MS m / z (ESI): 367.15 [M+1] + .

[0664] Second Step: Synthesis of compound 213

[0665] To a solution of compound 213b (50 mg, 0.14 mmol) in deuterated methanol (1 mL) was added at room temperature. The reaction mixture was stirred at 60 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% TFA); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 213 (20 mg). MS m / z (ESI): 368.10 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.38 (d, J = 8.8 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.70 (dd, J = 17.6, 7.2 Hz, 4H), 4.49 (dd, J = 18.0, 8.8 Hz, 4H), 3.71 - 3.66 (m, 1H), 2.68 - 2.62 (m, 1H), 1.74 - 1.65 (m, 1H), 1.61 - 1.54 (m, 1H).

[0666] Example 48 (Compound 215)

[0667] First Step: Synthesis of compound 215b

[0668] Hydrazine monohydrate (1.43 g, 28.54 mmol) was added to a solution of compound 215a (1.00 g, 7.92 mmol) in ethanol (10 mL) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction was cooled, filtered to get the filter cake which was washed with ethanol and dried under reduced pressure to get compound 215b (0.68 g). MS m / z (ESI): 127.05 [M+1] + .

[0669] Second Step: Synthesis of compound 215

[0670] N,N-dimethylformamide dimethyl acetal (89.8 mg, 0.75 mmol) was added to a solution of compound 215b (100.1 mg, 0.79 mmol) in 1,4-dioxane (1 mL) at room temperature. After the reaction mixture was stirred at 80 °C for 1 h, it was cooled to room temperature, and a solution of compound 23g (173.0 mg, 0.79 mmol) and acetic acid (95.3 mg, 1.58 mmol) in 1,4-dioxane (1 mL) was added. The reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid preparation chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 215 (24.9 mg). MS m / z (ESI): 335.90 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 11.18 (s, 1H), 8.62 (s, 1H), 7.84 (s, 1H), 7.72 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.27 (s, 1H), 2.60-2.54 (m, 1H), 1.66-1.48 (m, 2H).

[0671] Example 49 (compound 216)

[0672] First Step: Synthesis of compound 216b

[0673] Compound 216a (0.60 g, 4.54 mmol) and hydrazine hydrate (454.5 mg, 9.08 mmol) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at 90 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to obtain compound 216b (500 mg).

[0674] Second Step: Synthesis of compound 216

[0675] Compound 216b (150.0 mg, 1.14 mmol) and N,N-dimethylformamide dimethyl acetal (135.2 mg, 1.14 mmol) were added to a solution of 1,4-dioxane (6 mL), and the mixture was stirred at 80 °C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and acetic acid (68.1 mg, 1.14 mmol) and compound 23g (247.5 mg, 1.14 mmol) were added. The reaction mixture was stirred at 120 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (instrument model: SHIMADZU LC-20AP-3; column: Gemini5um C18 150*21.2mm; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 216 (32.0 mg). MS m / z (ESI): 341.75 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.50 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.59 (s, 1H), 3.88 - 3.79 (m, 1H), 2.93 (s, 2H), 2.58 - 2.52 (m, 1H), 1.72 - 1.60 (m, 1H), 1.60 - 1.49 (m, 1H), 1.20 (d, J = 15.6 Hz, 6H).

[0676] Example 50 (compound 217)

[0677] First Step: Synthesis of compound 217b

[0678] Hydrazine hydrate (833.6 mg, 16.65 mmol) was added to a solution of compound 217a (500 mg, 5.55 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 1 / 10) to give compound 217b (360 mg). MS m / z (ESI): 91.15 [M+1] + .

[0679] First Step: Synthesis of compound 217

[0680] Compound 217b (150 mg, 1.66 mmol) was added to a solution of N,N- dimethylformamide dimethyl acetal (198.4 mg, 1.66 mmol) in 1,4-dioxane (30 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 1 h, then cooled to room temperature. Acetic acid (99.9 mg, 1.66 mmol) and compound 23g (363.1 mg, 1.66 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C 18 150*21.2mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 217 (57.6 mg). MS m / z (ESI): 299.75 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.56 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 5.49 (s, 1H), 4.67 (s, 2H), 3.89 - 3.81 (m, 1H), 2.57 - 2.52 (m, 1H), 1.79 - 1.70 (m, 1H), 1.57 - 1.50 (m, 1H).

[0681] Example 51 (compound 218)

[0682] First Step: Synthesis of compound 218b

[0683] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 218a (1.17 g, 6.30 mmol) was stirred at 90 °C in molten state for 60 h. After the reaction was completed, the reaction solution was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to obtain compound 218b (600 mg, crude product), which was used directly in the next step without purification. MS m / z (ES): 454.00 [M+H] + .

[0684] Second Step: Synthesis of compound 218

[0685] Compound 218b (600 mg, crude product) was dissolved in hydrochloric acid dioxane solution (10 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: SHIMADZU LCMS-2020-2; column: Gemini 5um C18 150*21.2mm; mobile phase: 95% ACN / 5% H2O (containing 0.05% NH3); flow rate: 20 mL / min) to obtain compound 218 (39.7 mg). MS m / z (ESI): 353.90 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 3.78-3.72 (m, 1H), 3.13-3.02 (m, 4H), 2.79-2.68 (m, 4H), 2.57-2.53 (m, 1H), 1.65-1.60 (m, 2H).

[0686] Example 52 (compound 219)

[0687] First Step: Synthesis of compound 219b

[0688] At room temperature, 219a (106.3 mg, 0.34 mmol), 1,1-bis(diphenylphosphino)ferrocene palladium dichloride (20.9 mg, 0.02 mmol) and potassium carbonate (118.8 mg, 0.86 mmol) were added to a mixture of compound 214c (100 mg, 0.28 mmol) in 1,4-dioxane and water (1.0 mL / 0.1 mL) successively, and the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 219b (70 mg). MS m / z (ESI): 451.05 [M+1]+ .

[0689] Second Step: Synthesis of compound 219

[0690] Hydrochloric acid-1,4-dioxane (4.0 M, 1.0 mL) was added to compound 219b (60 mg, 0.13 mmol) at room temperature, the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 219 (25.7 mg). MS m / z (ESI): 350.95 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.26 (d, J = 4.0 Hz, 1H), 7.35 (d, J = 9.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 3.89 - 3.83 (m, 1H), 3.58 - 3.27 (m, 4H), 3.05 - 2.93 (m, 2H), 2.68 - 2.62 (m, 1H), 1.71 - 1.63 (m, 1H), 1.56 - 1.49 (m, 1H).

[0691] Example 53 (compound 220)

[0692] First Step: Synthesis of compound 220b

[0693] Hydrazine hydrate (0.33 mL, 5.45 mmol) was added to a solution of compound 220a (500 mg, 1.82 mmol) in ethanol (5 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH = 1 / 0 ~ 10 / 1) to give compound 220b (460 mg). MS m / z (ESI): 206.10 [M-55] + .

[0694] Second Step: Synthesis of compound 220c

[0695] Compound 220b (239.6 mg, 0.92 mmol) was added to a solution of N,N- dimethylformamide dimethyl acetal (109.3 mg, 0.92 mmol) in 1,4-dioxane (2 mL), the mixture was stirred at 80 °C for 1 h, then cooled to room temperature, compound 23g (200 mg, 0.92 mmol) and acetic acid (0.052 mL, 0.92 mmol) were added to the mixture, the reaction mixture was continued to stir at 110 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (DCM / MeOH = 1 / 0 ~ 10 / 1) to give compound 220c (70 mg). MS m / z (ESI): 470.95 [M+1] + .

[0696] Third Step: Synthesis of compound 220

[0697] Hydrochloric acid / 1,4-dioxane (4.0 M, 2 mL) was added to a solution of compound 220c (60 mg, 0.13 mmol) in 1,4-dioxane (1 mL), the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 220 (21.5 mg). MS m / z (ESI): 370.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) d 8.70 (s, 1H), 8.23 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.00 - 3.94 (m, 1H), 2.99 - 2.85 (m, 4H), 2.83 - 2.77 (m, 1H), 2.30 - 2.15 (m, 4H), 1.73 - 1.58 (m, 2H).

[0698] Example 54 (Compound 221)

[0699] First Step: Synthesis of compound 221

[0700] Compound 153 (50.0 mg, 0.13 mmol, synthesis method refer to synthesis of compound 153 in the second step of Reference Example 15) was added to a solution of deuterated methanol (2 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to obtain compound 221 (14.8 mg). MS m / z (ESI): 368.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 4.59 (d, J = 4.4 Hz, 1H), 3.88 - 3.76 (m, 1H), 3.51 - 3.40 (m, 1H), 2.96 - 2.82 (m, 1H), 2.56 - 2.52 (m, 1H), 1.99 - 1.84 (m, 4H), 1.72 - 1.64 (m, 1H), 1.64 - 1.51 (m, 3H), 1.32 - 1.13 (m, 2H).

[0701] Example 55 (compound 223)

[0702] First step: synthesis of compound 223b

[0703] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 223a (450 mg, 2.12 mmol) was stirred at 90 °C in a molten state for 16 hours. After the reaction was completed, the mixture was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 1 / 10) to obtain compound 223b (180 mg). MS m / z (ESI): 480.05 [M+1] + .

[0704] Second step: synthesis of compound 223c

[0705] Compound 223b (80 mg, 0.17 mmol) was added to a solution of deuterated methanol (1 mL), and the reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C 18150 * 21.2 mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 223c (30 mg). MS m / z (ESI): 481.10 [M+1] + .

[0706] Third Step: Synthesis of compound 223

[0707] Compound 223c (30 mg, 0.06 mmol) was added to a solution of hydrochloric acid-1,4-dioxane (4.0 M, 1 mL), and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was lyophilized to give compound 223 (20.7 mg). MS m / z (ESI): 381.05 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 7.31 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 4.26 - 4.16 (m, 2H), 4.08 - 3.91 (m, 2H), 3.80 - 3.70 (m, 1H), 3.69 - 3.51 (m, 2H), 2.81 - 2.68 (m, 1H), 2.35 - 2.25 (m, 1H), 2.23 - 2.09 (m, 3H), 2.00 - 1.89 (m, 1H), 1.84 - 1.74 (m, 1H).

[0708] Example 56 (compound 210)

[0709] First Step: Synthesis of compound 210a

[0710] Compound 201f (100 mg, 0.20 mmol, synthesis method refer to synthesis of compound 201f in Example 38, fourth step) was added to a solution of deuterated methanol (5 mL), and the reaction mixture was stirred at 60 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 210a (100 mg). MS m / z (ESI): 498.40 [M+1] + .

[0711] Second Step: Synthesis of compound 210

[0712] To a solution of compound 210a (100 mg, 0.20 mmol) in N,N-dimethylformamide (5 mL) was added cesium fluoride (152.3 mg, 1.00 mmol) at 90 °C. The reaction mixture was stirred at 90 °C for 2 h. After the reaction was completed, the reaction was filtered, and the filtrate was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 25-70%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 210 (28.6 mg). MS m / z (ESI): 383.80 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.28 (s, 1H), 3.78 - 3.73 (m, 1H), 3.29 - 3.23 (m, 1H), 3.22 - 3.08 (m, 3H), 2.56 - 2.51 (m, 1H), 1.70 - 1.55 (m, 3H), 1.52 - 1.41 (m, 3H), 1.12 (s, 3H).

[0713] Example 57 (compound 222)

[0714] First step: synthesis of compound 222b

[0715] To a solution of compound 222a (100 mg, 0.31 mmol) (synthesis method reference patent WO2023086575 A1 2023-05-19 specification page 43 compound H-Azepine-1-carboxylic acid, 2,3,4,7-tetrahydro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-, 1,1-dimethylethyl ester), compound 214c (107.9 mg, 0.31 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (45.2 mg, 0.06 mmol) and potassium carbonate (85.5 mg, 0.63 mmol) were added to a mixture solution of 1,4-dioxane and water (3 mL / 0.3 mL) at room temperature, and the reaction mixture was stirred at 90 °C for 16 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 222b (100 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 465.30 [M+1] + .

[0716] Step 2: Synthesis of compound 222

[0717] Compound 222b (100 mg, 0.21 mmol) was added to hydrochloric acid-1,4-dioxane solution (1 mL), the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C 18 150*21.2 mm; mobile phase: acetonitrile-water (0.1% FA); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 222 (21.8 mg). MS m / z (ESI): 364.85 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 8.74 (s, 1H), 8.50 (s, 1H), 7.27 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.50 (t, J = 6.0 Hz, 1H), 3.97-3.92 (m, 1H), 3.88 (d, J = 6.4 Hz, 2H), 3.43 (t, J = 5.8 Hz, 2H), 3.03-2.88 (m, 2H), 2.68-2.62 (m, 1H), 2.08-1.98 (m, 2H), 1.84-1.76 (m, 1H), 1.69-1.62 (m, 1H).

[0718] Example 58 (compound 174-P1, 224-P1)

[0719] Step 1: Synthesis of compound 174-P1

[0720] Compound 214c (0.30 g, 0.86 mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (99.5 mg, 0.17 mmol), cesium carbonate (840.2 mg, 2.58 mmol), tris(dibenzylideneacetone)dipalladium (88.97 mg, 0.086 mmol) and compound 224a (86.9 mg, 0.86 mmol) were dissolved in 1,4-dioxane (6 mL), and the reaction mixture was stirred at 110 °C for 18 hours. After the reaction was completed, the reaction was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1-3 / 1) to give compound 174-P1 (180 mg). MS m / z (ESI): 368.85 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.33 (dd, J = 8.8, 3.5 Hz, 1H), 6.82 (dd, J = 8.8, 4.7 Hz, 1H), 4.73 (s, 1H), 3.74 - 3.54 (m, 2H), 3.50 - 3.35 (m, 3H), 2.64 - 2.53 (m, 1H), 1.90 - 1.71 (m, 2H), 1.68 - 1.49 (m, 2H), 1.26 (d, J = 21.6 Hz, 3H).

[0721] Second Step: Synthesis of compound 224-P1

[0722] Compound 224b (150 mg, 0.41 mmol) was added into deuterated methanol (0.5 mL), the reaction mixture was stirred at 60 °C for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was purified by high performance liquid preparative chromatography (instrument model: SHIMADZU LC-20AP-1; column: Xbridge Prep C18 5um OBD; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to give compound 224-P1 (27.0 mg). MS m / z (ESI): 369.85 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.14 (d, J = 5.4 Hz, 1H), 7.33 (dd, J = 8.8, 3.5 Hz, 1H), 6.82 (dd, J = 8.8, 4.7 Hz, 1H), 4.73 (s, 1H), 3.74 - 3.54 (m, 2H), 3.50 - 3.35 (m, 3H), 2.64 - 2.53 (m, 1H), 1.90 - 1.71 (m, 2H), 1.68 - 1.49 (m, 2H), 1.26 (d, J = 21.6 Hz, 3H).

[0723] Example 59 (compound 174-P2, 224-P2)

[0724] First Step: Synthesis of compound 174-P2

[0725] To a solution of compound 214c (200 mg, 0.57 mmol) and compound 224b (57.9 mg, 0.57 mmol) in 1,4-dioxane (5 mL) were added tris(dibenzylideneacetone)dipalladium (52.4 mg, 0.057 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (66.3 mg, 0.12 mmol) and cesium carbonate (560.1 mg, 1.72 mmol). The reaction mixture was stirred at 110 °C for 18 h under nitrogen. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 90 / 10) to give compound 174-P2 (70 mg). MS m / z (ES): 369.05 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.14 (d, J = 5.9 Hz, 1H), 7.31 (dd, J = 8.8, 3.8 Hz, 1H), 6.80 (dd, J = 8.8, 5.1 Hz, 1H), 4.73 (s, 1H), 3.80 - 3.60 (m, 2H), 3.57 - 3.40 (m, 3H), 2.65 - 2.54 (m, 1H), 1.93 - 1.71 (m, 2H), 1.67 - 1.54 (m, 2H), 1.26 (d, J = 22.0 Hz, 3H).

[0726] Second Step: Synthesis of compound 224-P2

[0727] To a solution of compound 174-P2 (65 mg, 0.17 mmol) in deuterated methanol (10 mL) was added. The reaction mixture was stirred at 60 °C for 18 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (instrument model: SHIMADZU LCMS-2020-2; column: Gemini 5um C18 150*21.2mm; mobile phase: 95% ACN / 5% H2O with 0.1% FA; flow rate: 20 mL / min) to give compound 224-P2 (5.5 mg). MS m / z (ESI): 369.90 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.31 (d, J = 12.8 Hz, 1H), 7.34 (dd, J = 8.8, 2.8 Hz, 1H), 6.83 (dd, J = 8.8, 4.0 Hz, 1H), 4.73 (d, J = 13.6 Hz, 1H), 3.74 - 3.53 (m, 2H), 3.49 - 3.32 (m, 3H), 2.63 - 2.53 (m, 1H), 1.88 - 1.71 (m, 2H), 1.69 - 1.49 (m, 2H), 1.26 (d, J = 20.8 Hz, 3H).

[0728] Example 60 (Compound 225-P1)

[0729] First Step: Synthesis of compound 225b

[0730] Hydrazine hydrate (529.7 mg, 8.47 mmol) was added to a solution of compound 225a (500 mg, 4.23 mmol) in ethanol (10 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 3 / 1) to give compound 225b (400 mg). MS m / z (ESI): 119.1 [M+1] + .

[0731] Second Step: Synthesis of compound 225-P1

[0732] N,N-dimethylformamide dimethyl acetal (302.6 mg, 2.54 mmol) was added to a solution of compound 225b (300 mg, 2.54 mmol) in 1,4-dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 1 h. The reaction solution was cooled to room temperature, and a solution of compound 23g (830.7 mg, 3.81 mmol) and acetic acid (152.5 mg, 2.54 mmol) in 1,4-dioxane (5 mL) was added to the mixture, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 225-P1 (20.6 mg). MS m / z (ESI): 328.0 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.47 (d, J = 3.2 Hz, 1H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.85 (dd, J = 8.8, 2.0 Hz, 1H), 4.89 - 4.74 (m, 1H), 3.87 - 3.72 (m, 1H), 3.68 - 3.54 (m, 2H), 3.29 - 3.21 (m, 1H), 2.63 - 2.53 (m, 1H), 1.80 - 1.47 (m, 2H), 1.30 - 1.24 (m, 3H).

[0733] Example 61 (Compound 225-P2)

[0734] First Step: Synthesis of compound 225d

[0735] Hydrazine hydrate (847.5 mg, 16.93 mmol) was added to a solution of compound 225c (1.0 g, 8.46 mmol) in ethanol (20 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 3 / 1) to give compound 225d (500 mg). MS m / z (ESI): 117.15 [M-1] + .

[0736] Second Step: Synthesis of compound 225e

[0737] N,N-dimethylformamide dimethyl acetal (107.5 mg, 0.90 mmol) was added to a solution of compound 225d (106.6 mg, 0.90 mmol) in 1,4-dioxane (5 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 1 h. The reaction solution was then cooled to room temperature, a solution of compound 177a (300.0 mg, 0.90 mmol) and acetic acid (54.2 mg, 0.90 mmol) in 1,4-dioxane (5 mL) was added, and the reaction mixture was stirred at 120 °C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 225e (300 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 442.35 [M+1] + .

[0738] Third Step: Synthesis of compound 225-P2

[0739] Hydrochloric acid-1,4-dioxane (4.0 M, 5 mL) was added to a solution of compound 225e (300 mg, 0.67 mmol) in 1,4-dioxane (5 mL), and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to give compound 225-P2 (18.6 mg). MS m / z (ES): 327.80 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.47 (d, J = 2.8 Hz, 1H), 7.35 (dd, J = 8.8, 3.2 Hz, 1H), 6.85 (dd, J = 8.8, 2.4 Hz, 1H), 4.80 (s, 1H), 3.88 - 3.73 (m, 1H), 3.68 - 3.52 (m, 2H), 3.29 - 3.23 (m, 1H), 2.60 - 2.52 (m, 1H), 1.78 - 1.48 (m, 2H), 1.25 (dd, J = 6.8, 2.4 Hz, 3H).

[0740] Example 62 (compound 226)

[0741] First Step: Synthesis of compound 226b

[0742] Hydrazine hydrate (227.8 mg, 3.64 mmol) was added to a solution of compound 226a (450 mg, 1.82 mmol) in ethanol (5 mL), and the reaction mixture was stirred at 90 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 226b (400 mg). MS m / z (ESI): 192.15 [M-55] + .

[0743] Second Step: Synthesis of compound 226c

[0744] N,N-dimethylformamide dimethyl acetal (180.3 mg, 1.51 mmol) was added to a solution of compound 226b (374.2 mg, 1.51 mmol) in 1,4-dioxane (5 mL) at room temperature. After the reaction mixture was stirred at 90 °C for 1 h, the reaction was cooled to room temperature. Acetic acid (90.9 mg, 1.51 mmol) and compound 23g (330 mg, 1.51 mmol) were added. The reaction mixture was stirred at 120 °C for 18 h. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol = 5 / 1) to give compound 226c (200 mg). MS m / z (ESI): 457.25 [M+1] + .

[0745] Step 3: Synthesis of compound 226d

[0746] 1,4-dioxane (2 mL, 4.0 M) was added to a solution of compound 226c (180 mg, 0.39 mmol) in 1,4-dioxane (2 mL) at room temperature. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% NH3); gradient: 40-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 226d (65 mg). MS m / z (ESI): 357.15 [M+1] + .

[0747] Step 4: Synthesis of compound 226

[0748] Compound 226d (55 mg, 0.15 mmol) was added to a solution of deuterated methanol (2 mL). The reaction mixture was stirred at 50 °C for 18 h. After the reaction was completed, the reaction was concentrated under reduced pressure to give compound 226 (55 mg). MS m / z (ESI): 358.10 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.05 - 3.88 (m, 1H), 3.66 - 3.36 (m, 2H), 3.08 - 2.87 (m, 1H), 2.84 - 2.72 (m, 1H), 2.63 - 2.51 (m, 1H), 2.49 - 2.36 (m, 2H), 1.77 - 1.59 (m, 2H).

[0749] Example 63 (Compound 227-P1, P2)

[0750] First Step: Synthesis of Compound 227-P1, P2

[0751] Compound 8-P1 (70 mg, 0.20 mmol, for synthesis, please refer to Example 3, Step 3, synthesis of 8-P1) was added to a solution of deuterated methanol (2 mL) at room temperature, and the reaction mixture was heated to 50 °C and stirred for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 227-P1 or 227-P2 (25.9 mg). MS m / z (ESI): 354.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.37 - 3.17 (m, 3H), 2.91 - 2.78 (m, 2H), 2.06 - 1.94 (m, 2H), 1.92 - 1.78 (m, 2H), 1.76 - 1.67 (m, 1H), 1.56 - 1.47 (m, 1H).

[0752] Compound 8-P2 (90 mg, 0.26 mmol, for synthesis, please refer to Example 3, Step 3, synthesis of 8-P2) was added to a solution of deuterated methanol (2 mL) at room temperature, and the reaction mixture was heated to 50 °C and stirred for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography preparation (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 20-95%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 227-P2 or 227-P1 (27.8 mg). MS m / z (ESI): 354.05 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 3.84 - 3.79 (m, 1H), 3.45 - 3.17 (m, 3H), 2.99 - 2.80 (m, 2H), 2.50 - 2.45 (m, 1H), 2.12 - 1.99 (m, 2H), 1.97 - 1.82 (m, 2H), 1.77 - 1.65 (m, 1H), 1.60 - 1.46 (m, 1H).

[0753] Example 64 (Compound 228-P1, P2)

[0754] First Step: Synthesis of compound 220c-P1 and 220c-P2

[0755] Compound 220c (280 mg, synthesis method refer to the synthesis of compound 220c in example 53, step 2) was resolved by supercritical fluid chiral chromatography (equipment: SHIMADZU SFC-40P, column: Daicel Chiralpak AD-10 SFC 30 mm I.D.* 250 mm L, 10 pm, mobile phase: CO2 / MeOH [0.1% NH3(7M solution in MeOH)] 60 / 40, total flow rate: 100 ml / min) to give compound 220c-P1 (110 mg) and compound 220c-P2 (110 mg).

[0756] Compound 220c-P1: MS m / z (ESI): 470.90 [M+1] + . Super critical fluid chromatography SFC: Retention time = 2.725 min, UV = 214 nm.

[0757] Compound 220c-P2: MS m / z (ESI): 470.90 [M+1] + . Super critical fluid chromatography SFC: Retention time = 3.127 min, UV = 214 nm.

[0758] Second Step: Synthesis of compound 228a-P1 and 228a-P2

[0759] Compound 220c-P1 (200 mg, 0.23 mmol) was dissolved in deuterated methanol (3 mL), the reaction mixture was stirred at 60 °C for 18 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure to give compound 228a-P1 (100 mg, crude), the product was used directly in the next step reaction without purification. MS m / z (ESI): 471.95 [M+1] + .

[0760] Compound 220c-P2 (200 mg, 0.23 mmol) was dissolved in deuterated methanol (3 mL). The reaction mixture was stirred at 60 °C for 18 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 228a-P2 (100 mg, crude), which was used directly in the next step without purification. MS m / z (ESI): 472.00 [M+1] + .

[0761] Step 3: Synthesis of compounds 228-P1 and 228-P2

[0762] Compound 228a-P1 (100 mg, 0.21 mmol) was dissolved in hydrochloric acid-dioxane solution (5 mL), and the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 228-P1 (40.5 mg). MS m / z (ESI): 371.90 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.42 - 3.28 (m, 2H), 3.25 - 3.12 (m, 2H), 2.90 - 2.81 (m, 1H), 2.66 - 2.54 (m, 3H), 2.51 - 2.40 (m, 1H), 1.80 - 1.69 (m, 1H), 1.69 - 1.60 (m, 1H).

[0763] Compound 228a-P2 (100 mg, 0.21 mmol) was dissolved in hydrochloric acid-dioxane solution (5 mL). The reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was lyophilized to obtain compound 228-P2 (32.8 mg). MS m / z (ESI): 371.95 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.37 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.42 - 3.28 (m, 2H), 3.25 - 3.12 (m, 2H), 2.90 - 2.81 (m, 1H), 2.66 - 2.54 (m, 3H), 2.51 - 2.40 (m, 1H), 1.80 - 1.69 (m, 1H), 1.69 - 1.60 (m, 1H).

[0764] Example 65 (Compound 229)

[0765] Step 1: Synthesis of compound 229b

[0766] Compound 229a (500 mg, 1.84 mmol) and hydrazine hydrate (922.4 mg, 14.74 mmol) were dissolved in ethanol (5 mL), and the reaction mixture was stirred at 90 °C for 15 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to obtain compound 229b (421 mg). MS m / z (ESI): 202.10 [M-55] + .

[0767] Step 2: Synthesis of compound 229c

[0768] Compound 229b (280 mg, 1.09 mmol) and trimethyl orthoformate (230.9 mg, 2.18 mmol) were added to a solution in 1,4-dioxane (28 mL), and the reaction mixture was stirred at 45 °C for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature, and acetic acid (65.3 mg, 1.09 mmol) and compound 113a (252.5 mg, 1.09 mmol) were added, and the reaction mixture was stirred at 120 °C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 0-25%) to obtain compound 229c (200.0 mg). MS m / z (ESI): 481.35 [M+1] + .

[0769] Step 3: Synthesis of compound 229d

[0770] Boron tribromide (187.34 mg, 0.75 mmol) was added to a solution of compound 229c (120.0 mg, 0.25 mmol) in dichloromethane (6 mL) at 0 °C, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (instrument model: SHIMADZU LC-20AP-1; column: Xbridge Prep C18 5um OBD; mobile phase: ACN / H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 229d (60.0 mg). MS m / z (ESI): 366.85 [M+1] + .

[0771] Step 4: Synthesis of compound 229

[0772] Compound 229d (60 mg, 1.14 mmol) was added into a solution of deuterated methanol (2 mL), the reaction mixture was heated to 45 °C and stirred for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 229 (22.1 mg). MS m / z (ESI): 367.95 [M+1] + . 1 HNMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.69 - 3.60 (m, 1H), 3.51 - 3.42 (m, 1H), 3.30 - 3.16 (m, 3H), 2.66 - 2.57 (m, 1H), 2.36 - 2.17 (m, 3H), 2.13 - 1.90 (m, 3H), 1.84 - 1.68 (m, 2H).

[0773] Example 66 (Compound 232-P1)

[0774] First Step: Synthesis of compound 232b

[0775] A mixture of compound 214c (200 mg, 0.57 mmol) and compound 232a (853.9 mg, 8.0 mmol) was stirred at 100 °C in a melt state for 3 hours. After the reaction was completed, the reaction mixture was purified by silica gel column chromatography (dichloromethane / methanol = 90 / 10) to obtain compound 232b (220 mg, crude), which was used directly in the next step without purification. MS m / z (ES): 453.90 [M+H] + .

[0776] Second Step: Synthesis of compound 232-P1

[0777] Compound 232b (200 mg, crude) was dissolved in a hydrochloric acid-dioxane solution (10 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (instrument model: SHIMADZU LCMS-2020-2; column: Gemini 5um C18 150*21.2mm; mobile phase: 95% ACN / 5% H2O containing 0.1% FA; flow rate: 20 mL / min) to obtain compound 232-P1 (13.8 mg). MS m / z (ESI): 353.90 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.28 (s, 1H), 7.37 (d, J = 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 3.92 - 3.80 (m, 1H), 3.76 - 3.45 (m, 5H), 2.66 - 2.59 (m, 1H), 2.37 - 2.22 (m, 1H), 2.04 - 1.89 (m, 1H), 1.72 - 1.60 (m, 2H).

[0778] Example 67 (Compound 232-P2, 232-P2-1, P2-2)

[0779] First Step: Synthesis of compound 232d

[0780] A mixture of compound 214c (100 mg, 0.28 mmol) and compound 232c (320.2 mg, 1.72 mmol) was stirred at 100 °C in a melt state for 2 hours. After the reaction was completed, the reaction liquid was purified by silica gel column chromatography (dichloromethane / methanol = 1 / 0 ~ 10 / 1) to obtain compound 232d (70 mg). MS m / z (ESI): 454.10 [M+1] + .

[0781] Second Step: Synthesis of compound 232-P2

[0782] Hydrochloric acid-dioxane (4.0 M, 2 mL) was added to a solution of compound 232d (60 mg, 0.13 mmol) in 1,4-dioxane (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (preparative column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile-water (0.05% formic acid); gradient: 5-50%; column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 60 bar) to obtain compound 232-P2 (21.4 mg). MS m / z (ESI): 354.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.36 (d, J = 9.2 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H), 3.78 - 3.56 (m, 4H), 3.45 - 3.30 (m, 2H), 2.66 - 2.57 (m, 1H), 2.25 - 2.10 (m, 1H), 1.88 - 1.76 (m, 1H), 1.70 - 1.49 (m, 2H).

[0783] Step 3: Synthesis of compound 232-P2-1, 232-P2-2

[0784] Compound 232-P2 (20 mg) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IC-10 SFC, column: 30 mm I.D. * 250 mm L, 10 pm, mobile phase: 25% MeOH / CO2(NH4OH 0.1%), total flow rate: 90 mL / min) to give compound 232-P2-1 (4.11 mg) and compound 232-P2-2 (4.48 mg).

[0785] Compound 232-P2-1: MS m / z (ESI): 353.85, 355.65 [M+1, M+3] + Supercritical fluid chromatography SFC: Retention time = 8.95 min, UV = 214 nm.

[0786] Compound 232-P2-2: MS m / z (ESI): 353.80, 355.70 [M+1, M+3] + Supercritical fluid chromatography SFC: Retention time = 10.21 min, UV = 214 nm.

[0787] Example 68 (compound 177-P1, 177-P2)

[0788] Step 1: Synthesis of compound 177-P1, 177-P2

[0789] Compound 177 (80.0 mg, 0.23 mmol, synthesis method refer to Example 32, Step 6, synthesis of compound 177) was resolved by supercritical fluid chiral chromatography (column Daicel Chiralpak OJ-10 SFC; mobile phase: CO2: methanol (0.1% NH3); gradient: 15%; column temperature: 40 °C; flow rate: 80 mL / min; wavelength: 214 nm) to give compound 177-P1 (35.9 mg) and compound 177-P2 (33.4 mg).

[0790] Compound 177-P1: MS m / z (ESI): 354.85 [M+1] + Supercritical fluid chromatography SFC: Retention time = 2.769 min, UV = 214 nm. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.17 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.53 (s, 1H), 3.91 - 3.76 (m, 4H), 3.57 - 3.52 (m, 1H), 2.66 - 2.61 (m, 1H), 1.63 - 1.51 (m, 2H), 1.41 (s, 3H).

[0791] Compound 177-P2: MS m / z (ESI): 354.75 [M+1] + Supercritical fluid chromatography SFC: Retention time = 3.183 min, UV = 214 nm. 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.18 (s, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H), 5.53 (s, 1H), 3.92 - 3.76 (m, 4H), 3.58 - 3.52 (m, 1H), 2.55 - 2.53 (m, 1H), 1.62 - 1.50 (m, 2H), 1.41 (s, 3H).

[0792] Example 69 (Compound 198-P1)

[0793] First Step: Synthesis of compound 198b

[0794] Tert-butyldimethylsilyl chloride (1.93 g, 12.81 mmol), imidazole (1.82 g, 26.70 mmol) were added to a solution of compound 198a (2.0 g, 10.68 mmol) in dichloromethane (40 mL), the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction liquid was diluted with water (50 mL), extracted with dichloromethane (50 mL x 3), the combined organic phase was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 ~ 10 / 1) to obtain compound 198b (3.0 g). MS m / z (ESI): 246.15 [M-55] + .

[0795] Second Step: Synthesis of compound 198c

[0796] Compound 198b (1 g, 3.31 mmol) was added to a mixture of trifluoroacetic acid and dichloromethane (3 mL / 6 mL), and the reaction mixture was stirred at 0 °C for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, the residue was adjusted to pH = 8 with a saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (50 mL x 3), and the combined organic phase was concentrated under reduced pressure to give compound 198c (600 mg, crude). MS m / z (ESI): 202.10 [M+1] + .

[0797] Step 3: Synthesis of compound 198d

[0798] Compound 214c (200 mg, 0.57 mmol), {bis(cyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) mesylate (52.6 mg, 0.057 mmol), bis(cyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphane (29.4 mg, 0.057 mmol), cesium carbonate (560.1 mg, 1.72 mmol) were added to a solution of compound 198c (577.0 mg, 2.86 mmol) in 1,4-dioxane (10 mL) under nitrogen protection, and the reaction mixture was stirred at 100 °C for 16 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 198d (25 mg). MS m / z (ESI): 469.35 [M+1] + .

[0799] Step 4: Synthesis of compound 198-P1

[0800] Compound 198d (20.0 mg, 0.043 mmol) was added to a solution of hydrogen chloride-1,4-dioxane (2 mL, 4.0 M), and the reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (column: Gemini 5um C18 150*21.2mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 198-P1 (10.6 mg). MS m / z (ESI): 354.85 [M+1] + .1 H NMR (400 MHz, DMSO-d6) δ 10.38 - 10.28 (m, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 8.8, 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 3.2 Hz, 1H), 4.91 (dd, J = 12.4, 3.6 Hz, 1H), 4.35 - 4.25 (m, 1H), 3.73 - 3.66 (m, 1H), 3.65 - 3.56 (m, 1H), 3.56 - 3.40 (m, 2H), 3.37 - 3.33 (m, 1H), 2.65 - 2.55 (m, 1H), 2.01 - 1.88 (m, 1H), 1.83 - 1.73 (m, 1H), 1.63 - 1.52 (m, 2H).

[0801] Example 70 (Compound 198-P2)

[0802] First Step: Synthesis of compound 198f

[0803] Tert-butyldimethylsilyl chloride (1.93 g, 12.818 mmol), imidazole (1.82 g, 26.704 mmol) were added to a solution of compound 198e (2 g, 10.682 mmol) in dichloromethane (20 mL), the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 198f (3.0 g). MS m / z (ESI): 246.3 [M-55] + .

[0804] Second Step: Synthesis of compound 198g

[0805] Compound 198f (1 g, 3.317 mmol) was added to a mixed solution of trifluoroacetic acid and dichloromethane (5 mL / 10 mL), and the reaction mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the pH of the residue was adjusted to 8 with a saturated sodium bicarbonate solution, extracted with dichloromethane (50 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give compound 198g (720 mg). MS m / z (ESI): 202.10 [M+1] + .

[0806] Third Step: Synthesis of compound 198h

[0807] To a solution of compound 198g (600 mg, 1.72 mmol) in 1,4-dioxane (6 mL) were added compound 214c (1.73 g, 8.60 mmol), tris(dibenzylideneacetone)dipalladium (139.1 mg, 0.17 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (198.9 mg, 0.34 mmol), and cesium carbonate (1.12 g, 3.44 mmol) under nitrogen. The reaction mixture was stirred at 100 °C for 16 h. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (10 mL x 2), and the combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane / methanol = 1 / 0 ~ 9 / 1) to give compound 198h (110 mg). MS m / z (ESI): 469.30 [M+1] + .

[0808] Step 4: Synthesis of compound 198-P2

[0809] To a solution of compound 198h (100 mg, 0.21 mmol) in hydrogen chloride-1,4-dioxane (3 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (preparative column: Gemini5um C18 150*21.2mm; mobile phase: acetonitrile / water (0.1% formic acid); column temperature: 25 °C; flow rate: 20 mL / min; wavelength: 214 nm; column pressure: 80 bar) to give compound 198-P2 (17 mg). MS m / z (ESI): 355.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J = 11.6 Hz, 1H), 8.18 - 8.12 (m, 1H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 6.84 (dd, J = 8.8, 3.2 Hz, 1H), 4.91 (dd, J = 12.4, 3.6 Hz, 1H), 4.40 - 4.21 (m, 1H), 3.75 - 3.65 (m, 1H), 3.65 - 3.39 (m, 3H), 3.31 - 3.24 (m, 1H), 2.65 - 2.54 (m, 1H), 2.02 - 1.87 (m, 1H), 1.83 - 1.72 (m, 1H), 1.64 - 1.52 (m, 2H).

[0810] Example 71 (compounds 218-P1, 218-P2, 234-P1, 234-P2)

[0811] Step 1: Synthesis of compound 218b-P1, 218b-P2

[0812] Compound 218b (100 mg, synthesis method refer to the synthesis of compound 218b in the first step of example 51) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IB N-10 SFC, column: CHIRALPAK AD-H 250 mm*20 mm, 5 μm, mobile phase: 25% MeOH / CO2(NH4OH 0.1%) total flow rate: 70 mL / min) to give compound 218b-P1 (50 mg) and compound 218b-P2 (50 mg).

[0813] Compound 218b-P1: MS m / z (ESI): 454.15, 456.05 [M+1, M+3] + . Super critical fluid chromatography SFC: Retention time = 2.29 min, UV = 214 nm.

[0814] Compound 218b-P2: MS m / z (ESI): 454.15, 456.05 [M+1, M+3] + . Super critical fluid chromatography SFC: Retention time = 2.70 min, UV = 214 nm.

[0815] Step 2: Synthesis of compound 218-P1, 218-P2

[0816] Compound 218b-P1 (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane solution (2 mL), hydrochloric acid-1,4-dioxane solution (4.0 M, 0.55 mL, 2.20 mmol) was slowly added, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 218-P1 (31 mg). MS m / z (ESI): 354.15 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.77 - 10.56 (m, 1H), 9.71 - 9.41 (m, 2H), 9.02 - 8.86 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.05 - 6.89 (m, 1H), 3.92 - 3.81 (m, 1H), 3.79 - 3.60 (m, 4H), 3.33 - 3.11 (m, 4H), 2.74 - 2.65 (m, 1H), 1.87 - 1.76 (m, 1H), 1.67 - 1.56 (m, 1H).

[0817] Compound 218b-P2 (50 mg, 0.11 mmol) was dissolved in 1,4-dioxane solution (2 mL), hydrochloric acid-1,4-dioxane solution (4.0 M, 0.55 mL, 2.20 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 218-P2 (36 mg). MS m / z (ESI): 354.15 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.75 - 10.54 (m, 1H), 9.67 - 9.36 (m, 2H), 9.03 - 8.82 (m, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.03 - 6.90 (m, 1H), 3.90 - 3.81 (m, 1H), 3.78 - 3.58 (m, 4H), 3.30 - 3.12 (m, 4H), 2.74 - 2.64 (m, 1H), 1.86 - 1.76 (m, 1H), 1.66 - 1.56 (m, 1H).

[0818] Third step: synthesis of compound 234-P1, 234-P2

[0819] Compound 218-P1 (50 mg, 0.14 mmol) was added to a deuterated methanol (2 mL) solution, and the reaction mixture was stirred at 60°C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 234-P1 (22.0 mg). MS m / z (ESI): 355.05 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.60 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.79 - 3.61 (m, 4H), 3.22 (s, 4H), 2.75 - 2.63 (m, 1H), 1.87 - 1.74 (m, 1H), 1.69 - 1.53 (m, 1H).

[0820] Compound 218-P2 (50 mg, 0.14 mmol) was added to a deuterated methanol (2 mL) solution, and the reaction mixture was stirred at 60°C for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 234-P2 (18.2 mg). MS m / z (ESI): 355.0 [M+1] + . 1HNMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.50 (s, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.73 - 3.61 (m, 4H), 3.22 (s, 4H), 2.73 - 2.62 (m, 1H), 1.86 - 1.75 (m, 1H), 1.68 - 1.58 (m, 1H).

[0821] Example 72 (compounds 219-P1, 219-P2, 235-P1, 235-P2)

[0822] First Step: Synthesis of compounds 219b-P1, 219b-P2

[0823] Compound 219 (350 mg, synthesis method refer to the synthesis of compound 219b in example 52, first step) was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak AD-10 SFC; column: CHIRALPAK AD-10 250mm*30mm, 10 pm, mobile phase: 25% MeOH / C02(NH4OH 0.1%) total flow rate: 80 mL / min) to give compound 219b-P1 (150 mg) and compound 219b-P2 (150 mg).

[0824] Compound 219b-P1: MS m / z (ESI): 450.90 [M+1] + . Supercritical fluid chromatography SFC: Retention time = 2.57 min, UV = 214 nm.

[0825] Compound 219b-P2: MS m / z (ESI): 450.85 [M+1] + . Supercritical fluid chromatography SFC: Retention time = 3.34 min, UV = 214 nm.

[0826] Second Step: Synthesis of compounds 219-P1, 219-P2

[0827] Compound 219b-P1 (150 mg, 0.33 mmol) was dissolved in HC1-1,4-dioxane (4.0 M, 1.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 219-P1 (110 mg). MS m / z (ESI): 350.95 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 7.36 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.49 (s, 1H), 3.87 - 3.82 (m, 1H), 3.50 - 3.45 (m, 2H), 3.07 - 3.01 (m, 2H), 2.69 - 2.64 (m, 1H), 2.61 - 2.54 (m, 2H), 1.69 - 1.61 (m, 1H), 1.56 - 1.49 (m, 1H).

[0828] Compound 219b-P2 (150 mg, 0.33 mmol) was dissolved in HC1-1,4-dioxane (4.0 M, 1.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give compound 219-P2 (110 mg). MS m / z (ESI): 350.95 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.67 (s, 1H), 3.94 - 3.89 (m, 1H), 3.87 - 3.72 (m, 2H), 3.35 - 3.28 (m, 2H), 2.90 - 2.82 (m, 1H), 2.79 - 2.71 (m, 2H), 1.69 - 1.61 (m, 2H).

[0829] Third Step: Synthesis of compound 235-P1, 235-P2

[0830] Compound 219-P1 (35 mg, 0.10 mmol) was dissolved in deuterated methanol solution (5.0 mL), the reaction mixture was stirred at 60 °C for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 235-P1 (34.5 mg). MS m / z (ESI): 351.80 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.49 (s, 1H), 3.87 - 3.84 (m, 1H), 3.51 - 3.43 (m, 2H), 3.03 (d, J = 6.0 Hz, 2H), 2.74 - 2.57 (m, 3H), 1.74 - 1.62 (m, 1H), 1.58 - 1.47 (m, 1H).

[0831] Compound 219-P2 (75 mg, 0.21 mmol) was dissolved in deuterated methanol solution (5.0 mL), the reaction mixture was stirred at 60 °C for 48 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 235-P2 (41.8 mg). MS m / z (ESI): 351.80 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 8.8 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 6.62 (s, 1H), 3.88 - 3.84 (m, 1H), 3.84 - 3.67 (m, 2H), 3.37 - 3.27 (m, 2H), 2.90 - 2.81 (m, 1H), 2.78 - 2.69 (m, 2H), 1.68 - 1.55 (m, 2H).

[0832] Example 73 (Compound 220-P1, 220-P2)

[0833] First Step: Synthesis of compound 220-P1, 220-P2

[0834] Compound 220c-P1 (50 mg, 0.11 mmol, synthesis method refer to synthesis of compound 220c-P1 in the first step of Example 64) was dissolved in hydrochloric acid-1,4-dioxane solution (5 mL), the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 220-P1 (21.1 mg). MS m / z (ESI): 370.90 [M+1] + . 1H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.19 - 4.12 (m, 1H), 3.48 - 3.37 (m, 2H), 3.37 - 3.24 (m, 2H), 2.85 - 2.76 (m, 1H), 2.70 - 2.40 (m, 4H), 1.84 - 1.74 (m, 2H).

[0835] Compound 220c-P2 (50 mg, 0.11 mmol) was dissolved in hydrochloric acid-1,4-dioxane solution (5 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was freeze-dried to obtain compound 220-P2 (14.7 mg). MS m / z (ESI): 370.90 [M+1] + . 1 H NMR (400 MHz, CD3OD) δ 9.43 (s, 1H), 7.18 (d, J = 8.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 4.19 - 4.12 (m, 1H), 3.48 - 3.37 (m, 2H), 3.37 - 3.24 (m, 2H), 2.85 - 2.76 (m, 1H), 2.70 - 2.40 (m, 4H), 1.84 - 1.74 (m, 2H).

[0836] Example 74 (Compound 236-P1-1, 236-P1-2)

[0837] First Step: Synthesis of compound 236b

[0838] Cesium carbonate (37.3 mg, 0.12 mmol) compound 236a (206.6 mg, 200.3 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (99.5 mg, 0.17 mmol), tris(dibenzylideneacetone)dipalladium (78.7 mg, 0.086 mmol) were added to compound 214c (300 mg, 0.86 mmol) in 1,4-dioxane (6 mL) solution, and the reaction mixture was heated to 110°C under nitrogen protection and stirred for 18 hours. After the reaction was completed, the reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 2), and the combined organic phase was washed with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 0%-20%) to obtain compound 236b (100 mg).

[0839] MS m / z (ESI): 468.25 [M+1]+

[0840] Step 2: Synthesis of compound 236-P1-1, 236-P1-2

[0841] Compound 236c (100 mg, 0.22 mmol) was dissolved in dichloromethane (1 mL), hydrochloric acid-1,4-dioxane solution (1 mL) was added slowly, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction liquid was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (preparative column: Gemini 5um C18 150*21.2mm; flow rate 20 mL / min column temperature: room temperature; mobile phase: A: water (FA 0.1%) B: acetonitrile 35%) to obtain compound 236c (25 mg). The compound was resolved by supercritical fluid chiral chromatography (equipment: Daicel Chiralpak IB N-10SFC; column: CHIRALPAK AD-H 250mm*20mm, 5um; mobile phase: 25% MeOH / CO2(NH4OH 0.1%); total flow rate: 70 mL / min) to obtain compound 236-P1-1 (11.1 mg) and compound 236-P1-2 (11.0 mg).

[0842] Compound 236-P1-1: MS m / z (ESI): 368.10 [M+1] + Supercritical fluid chromatography SFC: Retention time = 5.829 min, UV = 214 nm. 1 H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.90-3.77 (m, 2H), 3.66-3.58 (m, 1H), 3.52-3.47 (m, 1H), 3.44-3.40 (m, 1H), 2.64-2.57 (m, 1H), 2.00-1.91 (m, 2H), 1.76-1.70 (m, 2H), 1.38 (s, 3H).

[0843] Compound 236-P1-2: MS m / z (ESI): 368.10 [M+1] + Supercritical fluid chromatography SFC: Retention time = 6.822 min, UV = 214 nm. 1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 3.83 - 3.78 (m, 1H), 3.74 - 3.68 (m, 2H), 3.56 - 3.53 (m, 1H), 3.39 - 3.35 (m, 1H), 2.66 - 2.58 (m, 1H), 1.98 - 1.92 (m, 2H), 1.79 - 1.65 (m, 2H), 1.33 (s, 3H).

[0844] The following compounds can be synthesized according to the preparation methods of the above examples.

[0845] Biological Examples

[0846] 1. Inhibition activity of compounds on potassium ion channel Kv1.3

[0847] Objective: To detect the inhibitory effect of compounds on the current of HEK-293 cell line stably expressing human Kv1.3 (KCNA3: NM_002232) channel using automatic patch clamp technology.

[0848] Test method:

[0849] 1) Cell culture: Kv1.3-HEK293 cell line was cultured in DMEM medium containing 10% fetal bovine serum, the culture temperature was 37°C, and the carbon dioxide concentration was 5%. When the cells were subcultured, the old culture medium was first removed and washed once with PBS, then 1 mL of 0.25%-Trypsin-EDTA solution was added, and incubated at 37°C for 1 minute. When the cells were detached from the dish bottom, 5 mL of 37°C preheated complete culture medium was added. The cell suspension was gently blown to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 minutes. For expansion or maintenance culture, the cells were seeded in 6 cm cell culture dishes, and the amount of cells seeded in each cell culture dish was 2.5 x 10 5 cells (final volume: 5 mL). Before automatic patch clamp detection, the cells were treated with TrypLE TMAfter separating the cells using Express culture medium to stop digestion, centrifuge, resuspend the cells, count them, and adjust the cell density to 2-3 × 10⁶ cells / year. 6 Cells / mL were collected, and then the cells were gently mixed on a balanced shaker for 15-20 minutes at room temperature before being analyzed.

[0850] 2) When performing electrophysiological assays using the fully automated patch-clamp QPatch 48X (Sophion) device, the prepared cells are first placed on the centrifuge of the Qpatch workbench. The cells are washed using multiple centrifugation / resuspension methods, and the cell culture medium is replaced with extracellular fluid. An MTP-96 plate is removed and placed in the MTP source position. A QPlate chip is removed and placed in the QPlate source position. The robotic arm scans the barcodes on the MTP-96 plate and the QPlate chip and then picks them up and transfers them to the measurement station. Intracellular fluid (145mM KF, 10mM HEPES, 10mM EGTA, 2mM MgCl2·6H2O, pH adjusted to 7.2 with KOH) and extracellular fluid (140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH) were aspirated from the liquid pools and added to the intracellular fluid pool and cell and compound pool of the QPlate chip. At the measurement station, all measurement sites on the QPlate underwent initial quality control. The quality control process included aspirating cell suspension from the centrifuge cell container and positioning the cells onto the chip wells using a pressure controller to establish a high-resistance seal, forming a whole-cell recording mode. Once a stable baseline control current is obtained, the test substance is aspirated from the MTP-96 plate and applied to the cells in a four-dose regimen, with each dose lasting at least 5 minutes. Blank control solution and working solution of the test compound are applied to the cells sequentially. The current detected in each cell in the solution without the compound serves as its control group. All electrophysiological experiments are performed at room temperature.

[0851] 3) The voltage stimulation protocol for whole-cell patch-clamp recording of Kv1.3 potassium current is as follows: After whole-cell sealing is achieved, the cell membrane voltage is clamped at -80mV, stepped to +40mV, and maintained for 500ms. Data is collected repeatedly every 20s to observe the effect of the drug on the peak value of Kv1.3 current.

[0852] Data Analysis:

[0853] The last dose in a multiple-dose series was used for data analysis. For each drug concentration, the average of the last three data points before the next dose was taken to represent the current value after that concentration. This average represents the current value (Id) for each drug concentration.compound ) and the reference current value (I control ) as blank control. Then the inhibition rate (%) of each drug concentration was calculated, i.e. inhibition rate (%) = (1 - I compound / I control )*100%. The mean (Mean), standard deviation (SD) and standard error (SE) of each concentration were calculated, and the data were expressed as Mean ± SE. The test results are shown in Tables 1 and 2. Wherein A represents: inhibition rate (%) ≥ 40%; B represents: 20% ≤ inhibition rate (%) < 40%; C represents: 10% ≤ inhibition rate (%) < 20%; D represents: inhibition rate (%) < 10%.

[0854] For the calculation of IC50, the IC50 value of each compound was calculated using Hill equation and the dose-effect curve was non-linearly fitted, i.e. Y = Bottom + (Top-Bottom) / (1+10^((LogIC50-X)*HillSlope)), wherein IC50 is the half-inhibition concentration. The calculation of IC50 and curve fitting were completed by using GraphPad Prism software. The test results are shown in Table 3.

[0855] Table 1

[0856] Table 2

[0857] Table 3

[0858] The above has exemplarily described the embodiments of the technical solutions of the present application. It should be understood that the protection scope of the present application is not limited to the above-mentioned embodiments. Any modification, equivalent replacement, improvement, etc. made by those skilled in the art within the spirit and principle of the present application shall be included in the protection scope of the claims of the present application.

Claims

A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: T is C 3-10 cycloalkyl, C 3-10 cycloalkenyl or 3-10 membered heterocyclyl, said C 3-10 cycloalkyl, C 3-10 cycloalkenyl or 3-10 membered heterocyclyl optionally substituted with one or more R 7 substituents; Ring A is a 5-10 membered heteroaryl; Z is OH; R 1 , R 2 , R 3 and R 4 are the same or different and each is independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano and amino; R 5 selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d -(CH2) r C(O)NR b R c , said C 1-6 1-6 carbon atoms, C 1-6 1-6 carbon atoms, C 3-12 1-6 carbon atoms, C 3-12 1-6 carbon atoms, C 3-12 1-6 carbon atoms, C 3-12 1-6 carbon atoms, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy, and 3-12 membered heterocyclylmercapto are optionally substituted with one or more R g ; R j and R k are the same or different and each is independently selected from H, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1- 6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; or R j and R k together with the atom to which they are attached form a 3-6 membered carbocyclic or 3-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; R g are the same or different and each is independently selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , NR b R c , -S(O)2R e , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 6 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl, 3-6 membered heterocyclyl, and 5-8 membered heteroaryl; or R 5 and one of R 6 or both R 6 form a 3-12 membered carbocyclic or heterocyclic ring with the atom to which they are attached, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1- 6cyanoalkyl, cyano, amino, oxo, C(O)R a , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 7 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or two R 7 with the atom to which it is attached forms a 3-6 membered carbocyclic or 3-6 membered heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a 3-12 membered carbocyclic or heterocyclic ring, which is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R a and R d are the same or different and each is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, OH, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R b and R c are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; Or R b and R c Together with the nitrogen atom attached thereto, they form a 4-8 membered heterocycle, wherein the 4-8 membered heterocycle is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R e selected from C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; n is 0, 1 or 2; r is 0, 1, 2, 3, 4, 5 and 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein, T is C 3-10 cycloalkyl or 3-10 membered heterocyclyl, said C 3-10 cycloalkyl or 3-10 membered heterocyclyl is optionally substituted with one or more R 7 substituents; Ring A is a 5-10 membered heteroaryl; Z is OH; R 1 , R 2 , R 3 and R 4 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano and C 3-6 cycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-6 cycloalkyl is optionally substituted with one or more substituents selected from halogen, OH, C 1- 6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano and amino; R 5 selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocyclylmercapto, -S(O)2R e -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d -(CH2) r C(O)NR b R c , said C 1-6 1-6 carbon atoms; and 1-6 alkyl, C 3-12 1-6 carbon atoms; and 3-12 cycloalkyl, C 3-12 1-6 carbon atoms; and g substituted with one or more R R j and R k are the same or different and each is independently selected from H, halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; or R j and R k together with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; R g are the same or different and each is independently selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , -S(O)2R e , C 3- 6cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 6 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or R 5 and one of R 6 , two R 6 with the atom to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3- 12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C(O)R a , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 7 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or two R 7 with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R a and R d are the same or different and each is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, OH, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R b and R c are the same or different and each is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; Or R b and R c Together with the nitrogen atom attached thereto, a 4-8 membered heterocyclic group is formed, wherein the 4-8 membered heterocyclic group is optionally selected from halogens, OH, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 It is substituted by one or more substituents selected from cyanoalkyl, cyano, amino, and oxo; R e selected from C 1-6 alkyl, C 1-6 haloalkyl, cyano, amino, C 1-6 cyanoalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; n is 0, 1 or 2; r is 0, 1, 2, 3, 4, 5 and 6. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, one or more of the following: (1) R 7 the same or different, each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1- 6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or two R 7 with the atom to which it is attached forming C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R is preferably selected from H, halogen, C 7 the same or different, and each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C(O)R a , cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; More preferably, R 7 are identical or different and each independently selected from the group consisting of H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano and amino; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; (3) R 1 (4) R 2 (5) R 3 and R 4 are the same or different and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, cyano, C 3-6 cycloalkyl and C 3-6 halocycloalkyl; (4) T is C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more R 7 substituents; (5) Ring A is a 5 membered heteroaryl; (6) R 5 is selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy, 3- to 12-membered heterocyclylmercapto, -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3- to 12-membered heterocyclyl, 3- to 12-membered heterocyclyloxy and 3- to 12-membered heterocyclylmercapto are optionally substituted with one or more R g ; R g are the same or different and each is independently selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy; R 6 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or R 5 and one of R 6 forms a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, characterized in that, one or more of the following: (1) Each of the "C" mentioned 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 aminoalkyl and C 1-6 The alkyl group in "cyanoalkyl" is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl, ethyl, isopropyl or sec-butyl; (2) each of the "C 1-6 alkyl and C 1-6 halogen in haloalkyl is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; (3) each of the "C 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 cycloalkyloxy and C 3-12 cycloalkylthio" is independently C 3-8 cycloalkyl, for example cyclopropyl, cyclobutyl or cyclopentyl; (4) each of the "3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl, 4-8 membered heterocyclyl, 3-10 membered heterocyclyl, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy" is independently N, O or S, for example N or O; the number of the heteroatoms is independently 1 or 2; (5) each of the "3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl and 3-10 membered heterocyclyl" is independently a 3-8 membered heterocyclyl; (6) each of the "3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl, 4-8 membered heterocyclyl, 3-10 membered heterocyclyl, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy" is independently a saturated or partially unsaturated monocyclic, bridged, fused or spiro ring; (7) each of the "5-10 membered heteroaryl and 5-8 membered heteroaryl" is independently a 5 membered heteroaryl; (8) in each of the "5-10 membered heteroaryl, 5-8 membered heteroaryl and 5 membered heteroaryl", the heteroatoms are independently N, O or S, preferably N and O, for example N; the number of the heteroatoms is independently 1, 2, 3 or 4, for example 2 or 3; (9) each said C 3-10 cycloalkenyl is independently C 5-6 membered cycloalkenyl; (10) each said C 2-6 alkenyl is independently C 2-4 alkenyl; and (11) each said C 2-6 alkynyl is independently C 2-4 alkynyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, one or more of the following: (1) each of said "C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 aminoalkyl, and C 1-6 cyanoalkyl" is independently methyl; (2) each said "C 1-6 alkyl and C 1-6 halogen in haloalkyl is independently fluorine; (3) each of the "C 3-12 cycloalkyl, C 3-10 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylthio, C 3-6 cycloalkyl and C 3- 6 cycloalkyloxy" is independently cyclopentyl or cyclopropyl; (4) each of the "3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, 3-12 membered heterocyclyl and 3-10 membered heterocyclyl" is independently a 4-8 membered heterocyclyl; (5) The heterocyclic group in each of the described "3-12-membered heterocyclic oxy group, 3-12-membered heterocyclic mercapto group, 3-12-membered heterocyclic group, 4-8-membered heterocyclic group, 3-10-membered heterocyclic group, 3-6-membered heterocyclic group and 3-6-membered heterocyclic oxy group" is independently aza-heterobutyl, oxoheterobutyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiaranyl, tetrahydropyranyl, piperidinyl, piperazineyl, morpholinyl and (6) each of the "5-10 membered heteroaryl, 5-8 membered heteroaryl and 5 membered heteroaryl" is independently selected from triazolyl, tetrazolyl, thiazolyl, pyrazolyl, imidazolyl and oxazolyl; (7) each said C 2-6 alkenyl is independently vinyl; and (8) each said C 2-6 alkynyl is independently ethynyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, characterized in that, one or two of the following: (1) T is selected from the group consisting of a is attached to phenyl; m is 0, 1, 2, 3, 4, 5, and 6; h is 0, 1, 2, 3, and 4; j is 0, 1, 2, 3, and 4; R 8 selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; and (2) R 5 selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylmercapto, -(CH2) r C(O)R a , -(CH2) r N(R b )C(O)R d and -(CH2) r C(O)NR b R c , said C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkyloxy, C 3-12 cycloalkylmercapto, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy and 3-12 membered heterocyclylmercapto are optionally substituted with one or more R g ; R g are the same or different and each is independently selected from halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, =NH, C(O)R a , N(R b )C(O)R d , C(O)NR b R c , C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy; R 6 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or R 5 and one of R 6 forms a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R 7 the same or different, and each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, and amino; or one of R 7 and R 5 , or one of R 7 and one of R 6 form, together with the atom to which they are attached, a C 3-12 cycloalkyl or 3-12 membered heterocyclyl, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, characterized in that, one or more of the following: (1) R 5 selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkyloxy, C 3-8 cycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylmercapto, -S(O)2R e , C(O)R a , -CH2-N(R b )C(O)R d , and -CH2-C(O)NR b R c , said C 1-6 1-6 alkyl, C 1-6 1-6 alkoxy, C 3-8 ycloalkyl, C 3-8 ycloalkyloxy, C 3-8 ycloalkylmercapto, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, 3-8 membered heterocyclyloxy, and 3-8 membered heterocyclylmercapto are optionally substituted with one or more R g ; Preferably, R 5 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1- 6-alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 3-8 membered heterocyclic oxygen group and 3-8 membered heterocyclic thiol group are optionally surrounded by one or more R g replace; (2) R 6 the same or different, each independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1- 6 hydroxyalkyl, OH, cyano, amino, -S(O)2R e , C 3-6 cycloalkyl and 3-6 membered heterocyclyl; R is preferably selected from the group consisting of H, deuterium, halogen, C 6 the same or different, and each independently selected from the group consisting of H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; and (3) R 1 (2) R 2 (1) R 3 and R 4 are the same or different and each independently selected from H, halogen, C 1-6 alkyl, cyano and C 2-6 alkynyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, characterized in that, one or more of the following: (1) T is selected from the group consisting of a is attached to the phenyl; j is 0, h is 0, m is 0, 1 or 2, R 7 is deuterium, halogen, C 1-6 alkyl, C 1-6 hydroxyalkyl, C 1-6 cyanoalkyl, -C 1-6 alkylene-3-6 membered heterocyclyl or 3-6 membered heterocyclyl; (2) Ring A is selected from triazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, pyridyl, for example triazolyl, imidazolyl, pyrazolyl, isoxazolyl, tetrazolyl and pyridyl; (3) R 5 selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, C 3-12 cycloalkyloxy, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, 3-12 membered heterocyclyloxy, 3-12 membered heterocyclylthio, -(CH2) r C(O)R a -(CH2) r N(R b )C(O)R d -(CH2) r C(O)NR b R c , said C 1-6 1-6C-alkyl, C 1-6 1-6C-alkoxy, C 3-12 3-7C-cycloalkenyl, C 3-12 3-7C-cycloalkyl, C 3- 12 3-12C-heterocyclyl are optionally substituted by one or more R g ; R j and R k together with the atom to which they are attached form a 3-6 membered heterocyclic ring; R g the same or different, and each independently selected from the group consisting of halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, amino, oxo, =NH, C(O)R a , NR b R c , 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy, said C 1-6 alkyl and 3-6 membered heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halogen and C 1-6 alkoxy; R a and R d are the same or different and each is independently selected from C 1-6 alkyl and 3-6 membered heterocyclyl; R b and R c is selected from the group consisting of H and C 1-6 alkyl, or R b and R c together with the nitrogen atom to which they are attached form a 4-8 membered heterocyclic ring; said 4-8 membered heterocyclic ring is optionally substituted with one or more substituents selected from the group consisting of OH and C 1-6 alkyl; r is 0 or 1; (4) R 6 the same or different, and each independently selected from the group consisting of deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, cyano, -S(O)2R e and C 3-6 cycloalkyl; R e selected from C 1-6 alkyl; n is 0 or 1; (5) when R 5 and the R 6 adjacent thereto, or two adjacent R 6 , and the atoms to which they are attached form a 5-10 membered heterocyclic ring, said 5-10 membered heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of C 1-6 alkyl, C 1-6 hydroxyalkyl and -C(O)-C 1-6 alkyl; and (6) when R 7 and R 5 , or R 7 and R 6 , and the atoms to which they are attached form a ring, then the ring is a 5-10 membered heterocyclic ring. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, characterized in that, one or more of the following: (1) T is (2) Ring A is triazolyl or imidazolyl; (3) R 5 selected from H, C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl, 3-12 membered heterocyclyl, 5-8 membered heteroaryl, said C 1-6 alkyl, C 3-12 cycloalkyl, C 3-12 cycloalkenyl and 3-12 membered heterocyclyl are optionally substituted with one or more R g R g are the same or different, and each is independently selected from -NH2, halogen, OH, C 1-6 alkyl, C 1-6 haloalkyl and oxo; (4) R 6 the same or different, and each independently selected from the group consisting of deuterium, halogen and C 1-6 alkyl; n is 0 or 1 ; and (5) R 1 (6) R 2 (7) R 3 and R 4 are the same or different and each is independently selected from H, halogen and cyano. The compound or pharmaceutically acceptable salt thereof according to claim 1, characterized in that, one or more of the following: (1) For (2) T is Preferably (3) Ring A is selected from Preferably (4) R 6 selected from CH3, CN, (CH2)3OH, CHF2, CF3, Cl, S(O)2CH3, Br, D, F and cyclopropyl; n is 0 or 1; (5) when R 5 and one R 6 adjacent to it, or two adjacent R 6 , together with the atoms to which they are attached, form a ring, which is represents a bond shared with Ring A; (6) when R 7 and R 5 , or R 7 and R 6 , and the atoms to which they are attached form a ring, then it is a * denotes a position common to T, represents a bond shared with Ring A; and (7) R 5 selected from H, (CH2) t NH2, O-(CH2) t NH2, (CH2) t OH, cyclopropyl, The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein the compound is a compound according to Formula (IIG): wherein, G is selected from the group consisting of absent, CR 7b R 7c , NR 7e , O, and S; u is 1 and 2; v and m are independently 0, 1 and 2; R 7a , R 7b , R 7c and R 7d are the same or different and each is independently selected from H, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, OH, cyano, amino, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 7e selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 cyanoalkyl, C 1-6 aminoalkyl, C 1-6 hydroxyalkyl, -C 1-6 alkylene-3-6 membered heterocyclyl, C 3-6 cycloalkyl and 3-6 membered heterocyclyl; or R 7b and R 7c with the atom to which they are attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl, said C 3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, and oxo; or R 7a and R 5 , or R 7a and wherein any one of the groups of R 6 together with the atoms to which they are attached form a C 3-12 cycloalkyl or 3-12 membered heterocyclyl group, said C 3-12 cycloalkyl or 3-12 membered heterocyclyl group being optionally substituted with one or more substituents selected from halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , ring A and n are as defined in any one of claims 1-10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-11, wherein the compound is a compound according to formula (II): wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , ring A and n are as defined in any one of claims 1-11; R 7a , R 7b , R 7c and R 7d are as defined in claim 11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-12, wherein the compound represented by Formula (I) is a compound represented by Formula (II-1), Formula (II-2), or Formula (II-3), wherein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b , R c , R d and R g as defined in any one of claims 1-12; R 7a , R 7b , R 7c and R 7d as defined in claim 11 or 12; Preferably, R 7a , R 7b , R 7c and R 7d are the same or different and each independently selected from the group consisting of H, F, CH3, CH2OH, CH2CN, azetidinyl, piperidinyl and Preferably, R 5 Selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl thiol, 3-8 membered heterocyclic group, 5-8 membered heteroaryl, 3-8 membered heterocyclic oxy group, 3-8 membered heterocyclic thiol group, C(O)R a -CH2-N(R) b )C(O)R d and -CH2-C(O)NR b R c The C mentioned 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkyloxy, C 3-8 Cycloalkyl mercapto, 3-8 membered heterocyclic group, 5-8 membered heteroaryl group, 3-8 membered heterocyclic oxy group and 3-8 membered heterocyclic mercapto group are optionally surrounded by one or more R g replace; Preferably, R 6 They may be the same or different, and each is independently selected from H, deuterium, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, OH, cyano, amino, C 3-6 cycloalkyl and 3-6 membered heterocyclic groups; or, in formula (II-1) R 7a and R 5 form a 4-12 membered heterocyclyl with the atom to which they are attached; or, in formula (II-2) R 7a and R 5 , or R 5 and any group of its adjacent R 6 form a C 3-12 cycloalkyl or 4-12 membered heterocyclyl; or R 7a and R 6 , or R 5 and R 6 form, together with the atom to which they are attached, a 4-12 membered heterocyclyl group; C 3-12 Cycloalkyl or 4-12 membered heterocyclyl is optionally substituted with one or more substituents selected from halogen, OH, C 1-6 C1-C6alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, cyano, amino, oxo, C 3-6 cycloalkyl, and 3-6 membered heterocyclyl. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-13, wherein the compound represented by Formula (I) is a compound represented by Formula (III), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and T are as defined in any one of claims 1 to 13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-14, wherein, The compound has the structure: The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-15, wherein the compound is selected from the following compounds: A compound of Formula (C) or a pharmaceutically acceptable salt thereof, wherein R A is a hydroxyl protecting group, such as methyl, (trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl, methoxymethyl, 2-methoxyethoxymethyl, or 2-tetrahydropyran; R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof according to claim 17, wherein the compound of Formula (C) is selected from the following compounds: A preparation method of a compound of formula (IIIA) comprises that a compound of formula (A) is subjected to a ring closure reaction with a compound of formula (B) to obtain a compound of formula (C1), and then a deprotection group reaction is performed to obtain the compound of formula (IIIA), and the reaction formula is as follows: wherein R A is a hydroxyl protecting group, for example methyl, (trimethylsilyl)ethoxymethyl, tert-butyldimethylsilyl, methoxymethyl, 2-methoxyethoxymethyl or 2-tetrahydropyran; R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Use of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for inhibiting Kv1.3 channel. Use of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for preventing and / or treating a Kv1.3 channel-mediated disease; preferably, the Kv1.3 channel-mediated disease is an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease, or a cancer; further preferably, the Kv1.3 channel-mediated disease is rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, kidney fibrosis, inflammatory neuropathy, and ischemic stroke. Use of a compound according to any one of claims 1-16, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20, for the manufacture of a medicament for preventing and / or treating an autoimmune disease, an inflammatory disease, a metabolic disease, a cardiovascular disease, a kidney disease, a central nervous system disease, or a cancer, such as for preventing and / or treating rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, arthritis, spondylitis, periodontitis, psoriasis, diabetes, inflammatory bowel disease, ulcerative colitis, Crohn's disease, nephritis, chronic kidney disease, kidney fibrosis, inflammatory neuropathy, and ischemic stroke.

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